Impact of Molecular Testing on Improved Diagnosis, Treatment and Management of CAP

Study Overview
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Brief Summary
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Investigators will recruit patients suspected of community-acquired pneumonia at Haukeland University Hospital, Bergen, into a pragmatic randomized controlled trial to assess if provision of ultra-rapid, high-quality accurate molecular diagnostics with direct feedback to the clinician can facilitate pathogen-directed usage of antibiotics, shorten antibiotic exposure and admission time and is safe. Additionally, transcriptional and immune marker profiling of patients will guide appropriate management through a targeted focus on the individual patient's physical capacity, nutritional status and co- morbidities. The pragmatic design of this trial together with broad inclusion criteria and a straightforward intervention would make our results generalisable to other similar centres.

Detailed Description
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The study is a pragmatic, single-blind, single-centre randomised controlled trial (RCT) where community-acquired pneumonia (CAP) patients will receive standard of care microbiological testing or standard of care microbiological testing and comprehensive ultra-rapid molecular testing (UR-MT). Investigators will over a 3-year period (2020-2022), consecutively enroll cases of CAP admitted ( 900/year) to Haukeland University Hospital (HUS, Bergen). The study will consist of representative patients admitted with CAP and thus, will potentially be generalisable to hospitalised patients with CAP in Norway. As COVID-19 cannot be distinguished clinically from other pneumonias, the study will therefore include patients with suspected CAP, including with COVID-19. Approximately 1500 CAP patients will be screened to achieve a total of 1060 (allowing for a 10% dropout rate) enrolled patients that are randomly assigned to receive standard of care microbiological testing or standard of care testing microbiological and the comprehensive ultra-rapid molecular test (UR-MT). Inclusion criteria for the study are: adults (aged ≥18 years), with a clinical diagnosis of CAP (presence of at least two clinical criteria [new/worsening cough, new/worsening expectoration of sputum, haemoptysis, new/worsening dyspnoea, pleuritic chest pain, fever, or abnormalities on chest auscultation or percussion] or one clinical criterion and radiological evidence of CAP), requiring hospitalisation to a non-ICU ward, and with a capacity to give informed written consent or consent provided by the patient's legally authorized representative. Exclusion criteria include: lung tumour, cystic fibrosis, a palliative approach, patients who decline to provide respiratory tract specimens, severe immunodeficiency, and hospitalization for two or more days in the last 14 days. Based on clinical evaluation and data of admission, patients will be triaged for severity according to current risk assessment guidelines, as well as the CRB-65 score for the assessment of severity of pneumonia. Randomization of CAP patients to the two treatment arms (1:1) will be performed in blocks of size 4, 6, or, 8, occurring in random order, to ensure approximately equal allocation over the year. The prescribed empirical therapy for each patient will be compared with what antimicrobial(s) would have been appropriate for pathogen-directed therapy, based on the UR-MT result. Appropriate pathogen-directed therapy will be determined using national guidelines recommended by the Norwegian directorate of health

Official Title
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Impact of Molecular Testing on Improved Diagnosis, Treatment and Management of CAP in Norway: a Pragmatic Randomised Controlled Trial

Conditions
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Pneumonia

Intervention / Treatment
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* Diagnostic Test: Ultra-rapid molecular point-of-care testing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults (aged ≥18 years), Clinical diagnosis of CAP (presence of at least two clinical criteria [new/worsening cough, new/worsening expectoration of sputum, haemoptysis, new/worsening dyspnoea, pleuritic chest pain, fever, or abnormalities on chest auscultation or percussion] or one clinical criterion and radiological evidence of CAP) Requiring hospitalisation to a non-ICU ward Capacity to give informed written consent or consent provided by the patient's legally authorized representative. Exclusion Criteria: Pulmonary embolism Lung tumor Cystic fibrosis Palliative approach Patients who decline to provide respiratory tract specimens Severe immunodeficiency Hospitalization for two or more days in the last 14 days

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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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A pragmatic, parallel-arm, single-blinded, single-centre, randomised controlled superiority trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Ultra-rapid molecular point-of-care testing<br>Extended and more rapid diagnostics on microbiological specimens and an active feedback to treating staff with results. | Diagnostic Test: Ultra-rapid molecular point-of-care testing<br>* Ultra-rapid molecular testing (UR-MT) comprises automated detection using the new BioFire® FilmArray® Pneumonia plus platform (Biomérieux). The total turn-around time is <2 hrs. The UR-MT is combined with standard of care, comprising: Microbiological processing per current standard of care entails culture of respiratory tract samples according to national protocols to detect respiratory bacteria, identified using biochemical methods and/or matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF MS). Respiratory viruses are identified using real-time PCR (for metapneumovirus, rhinovirus, influenza A, influenza B, parainfluenza 1-3, RSV and SARS-CoV-2). The total turn-around time is up to 48 hrs.<br>* Other names: BioFire® FilmArray® Pneumonia plus platform (Biomérieux);|
| No Intervention: Standard of care<br>Standard collection of microbiological specimens and standard reply to treating staff. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The provision of pathogen-directed treatment based on a microbiological test result deemed as clinically relevant within 48 hours of receipt of respiratory samples. | Binary outcome: yes: it was provided/no: it was not provided | Up to 72 hours | 
| Time in hours from receipt of respiratory specimens to receiving pathogen-directed treatment | Quantitative outcome (measured in hours): time from receipt of respiratory specimens to provision of pathogen-directed treatment based on a microbiological test result deemed as clinically relevant or an elapse of 48 hours, whichever event came first. | Up to 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of antibiotic use in days | Duration of antibiotic use in days | Up to 4 weeks | 
| Proportion of patients receiving narrow-spectrum antibiotics within 48 hours from study inclusion | Proportion of patients receiving narrow-spectrum antibiotics within 48 hours from study inclusion | Up to 4 weeks | 
| Proportion of patients receiving a single dose of antibiotics | Proportion of patients receiving a single dose of antibiotics | Up to 1 week | 
| Proportion of patients receiving ≤48 h of antibiotics | Proportion of patients receiving ≤48 h of antibiotics | Up to 1 week | 
| Proportion of patients receiving intravenous antibiotics | Proportion of patients receiving intravenous antibiotics | Up to 1 week | 
| Duration of intravenous antibiotics in days | Duration of intravenous antibiotics in days | Up to 4 weeks | 
| Proportion of cases where the UR-MT results were used to guide treatment | Proportion of cases where the UR-MT results were used to guide treatment | Up to 1 week | 
| Time in days to isolation or de-isolation | Time in days to isolation or de-isolation | Up to 2 weeks | 
| Duration of door-to-needle time in hours | Duration of door-to-needle time in hours | Up to 1 week | 
| Length of hospital stay in days | Length of hospital stay in days | Up to 3 months | 
| Proportion of 30-day readmission | Proportion of 30-day readmission | Up to 30 days from discharge | 
| Proportion of 30- and 90-day and 1- and 5 year mortality | Proportion of 30- and 90-day and 1- and 5 year mortality | Up to 1 month, 3 months, 1 and 5 years, from admission | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Microbiology, Bacteria and viruses, Rapid diagnosis, Antibiotic resistance, Diagnostic stewardship