Clinical Evaluation of a Point of Care (POC) Assay to Identify Phenotypes in the Acute Respiratory Distress Syndrome

Study Overview
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Brief Summary
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Patients prospectively classified to the hyper-inflammatory ARDS phenotype on the basis of clinical characteristics and a novel POC biomarker assay will have worse clinical outcomes than the hypo-inflammatory phenotype. Study Aim The purpose of this project is to prospectively identify hyper- and hypo-inflammatory phenotypes in patients with ARDS and determine clinical outcomes associated with each phenotype. The primary objective of this study is to assess the clinical outcomes in patients with ARDS according to their prospectively defined inflammatory phenotype determined using a POC assay. Results of group allocation will be blinded to clinical and research staff until database lock. Secondary Objectives The secondary objectives of this study are to: (i) Assess the agreement of the phenotype allocation using the POC assay and the clinical study dataset. (ii) Assess the stability of phenotype allocation over time (iii) To test feasibility of delivering a POC assay in the NHS intensive care setting.

Detailed Description
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Acute respiratory distress syndrome (ARDS) is an inflammatory condition that results in severe respiratory failure and the need for mechanical ventilation. It is a syndrome with significant global burden and accounts for approximately 24% of mechanically ventilated patients in intensive care units. It is estimated to account for approximately 75000 deaths annually in the USA alone. Despite decades of research, mortality due to ARDS remains high at 35-46%, with increasing mortality in patients with more severe lung injury. ARDS survivors have significant long term comorbidity with reduced quality of life even 5 years after disease resolution. Various pharmacological agents such as β2 agonists, statins, keratinocyte growth factor and aspirin have been investigated as potential therapies to prevent or treat ARDS, however to date there is no effective pharmacological therapy for ARDS and current treatment strategy is largely supportive. One reason for the lack of specific pharmacological therapy is likely due to the clinical and biological heterogeneity. It is essential to rapidly identify patients with specific therapy responsive traits to improve our chance of identifying a specific therapy. Rationale for the Study ARDS phenotypes have different outcomes and response to therapy. The clinical and biological heterogeneity in ARDS makes it essential to identify homogenous phenotypes when investigating potential therapies. A retrospective analysis of the clinical and biological data-set collected as part of two large multicentre studies (ARMA and ALVEOLI) using latent class analysis has identified at least two ARDS phenotypes. Furthermore these two phenotypes could be differentiated using a parsimonious data-set including the presence of shock, metabolic acidosis and a higher inflammatory status (IL-6 and sTNFr1). The hyper-inflammatory phenotype demonstrated significantly worse outcomes when compared to the hypo-inflammatory phenotype with higher mortality and less ventilator free and organ failure free days. In the ALVEOLI study, where low PEEP was compared to high PEEP strategy, the two phenotypes demonstrated a differential response to PEEP suggesting the potential for using this phenotypic classification in identifying a therapy responsive trait. In addition, in a secondary analysis of the HARP-2 study, a multicentre study investigating the potential of simvastatin as an anti-inflammatory therapy for ARDS, the presence of a hyper- and hypo-inflammatory phenotype was confirmed. The hyper-inflammatory phenotype had a higher 28 day mortality, fewer ventilator free days and organ failure free days. Survival of patients classified as hyper-inflammatory and randomised to simvastatin was improved. Implementation of a precision medicine approach to identify patients with a therapy response trait is crucial to identify specific therapies to prevent or treat ARDS. Development of a Point of Care (POC) assay for IL-6 and sTNFr1 for prospective confirmation of the inflammatory phenotypes using the parsimonious data-set in patients with ARDS will support a precision medicine approach for this condition. A POC assay will support precision medicine for ARDS Studies that show no benefit from an intervention could occur as a result of a variety of reasons including a) the intervention was ineffective, b) the study design was poor or c) patient heterogeneity. Reduction of patient heterogeneity to identify patients with common biological processes will enable the selection of patients with a higher likelihood of therapy response in clinical studies. The identification and institution of therapy for critically ill patients with ARDS needs to occur rapidly in view of the nature of the disease and development of an accurate POC assay is likely to be an essential component in the discovery of effective therapies.

Official Title
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Clinical Evaluation of a POC Assay to Identify Phenotypes in the Acute Respiratory Distress Syndrome

Conditions
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Acute Respiratory Distress Syndrome (ARDS)

Intervention / Treatment
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* Diagnostic Test: POC Assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is receiving mechanical ventilation or high flow nasal oxygen (HFNO) ARDS as defined by the Berlin definition (Ranieri et al.) a) Onset within 1 week of identified insult b) Within the same 24-hour time period: i. Hypoxic respiratory failure (PaO2/ FiO2 ratio ≤ 40kPa on PEEP ≥ 5 cmH20*) ii. Bilateral infiltrates consistent with pulmonary oedema not explained by another pulmonary pathology iii. Respiratory failure not fully explained by cardiac failure or fluid overload The time of onset of ARDS is when the last ARDS criterion is met. *PEEP assumed ≥ 5 cmH20 if on HFNO. Exclusion Criteria: Age <18 years of age More than 48 hrs after onset of ARDS Receiving ECMO at the time of recruitment Treatment withdrawal imminent within 24 hours DNAR (Do Not Attempt Resuscitation) order (excluding advance directives) in place Declined consent Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adults in the Intensive Care Setting<br>Adults in the Intensive Care Setting | Diagnostic Test: POC Assay<br>* Interventions: Blood Baseline - up to 40ml Day 3 - up to 40ml Urine Baseline - 10ml Day 3 - 10ml Study population: Adults (18 plus) in ICU units diagnosed with ARDS.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is mortality at 60 days in the hyper-inflammatory and hypo-inflammatory phenotypes in patients with ARDS. | The primary outcome is mortality at 60 days in the hyper-inflammatory and hypo-inflammatory phenotypes in patients with ARDS. | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in time to extubation | Difference in time to extubation | 60 days | 
| Intubation rate in patients on HFNO | Intubation rate in patients on HFNO | 60 days | 
| Reintubation Rate | Reintubation Rate | 60 days | 
| Number of ventilator free days at day 28 | Number of ventilator free days at day 28 | 28 days | 
| Number of days on ventilation | Number of days on ventilation | 60 days | 
| Length of ICU stay | Length of ICU stay | 60 days | 
| Length of hospital stay | Length of hospital stay | 60 days | 
| Mortality at day 28 | Mortality at day 28 | 28 days | 
| Agreement of phenotype classification using a POC assay and standard laboratory based assays. | Agreement of phenotype classification using a POC assay and standard laboratory based assays. | Day 1 and day 3 | 
| Agreement of phenotype classification using a POC assay and the clinical study dataset. | Agreement of phenotype classification using a POC assay and the clinical study dataset. | 2 Years | 
| Agreement of phenotype classification between day 1 and day 3. | Agreement of phenotype classification between day 1 and day 3. | Day 1 and Day 3 | 
| Frequency of assay technical failure rate will be used to determine the feasibility of delivering a POC assay in NHS intensive care setting. | Frequency of assay technical failure rate will be used to determine the feasibility of delivering a POC assay in NHS intensive care setting. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyper and hypo-inflammatory, Phenotypes, POC (point of care)