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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Respiratory Distress Syndrome (ARDS)
• Intervention / Treatment: Diagnostic test: POC Assay

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 480

Contacts and Locations

• Study Contact: Name: Lynn Murphy; Phone Number: 02896 151451; Email: lynn.murphy@nictu.hscni.net
• Study Contact Backup: Name: Pauline Bradley; Phone Number: 02896 151242; Email: PaulineA.Bradley@nictu.hscni.net

Study Locations

• Ireland
  • Dublin, Ireland, D04 T6F4
    • St Vincents Hospital
• United Kingdom
  • Belfast, United Kingdom
    • Royal Victoria Hospital
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital
  • London, United Kingdom
    • Imperial College London
  • Oxford, United Kingdom
    • Oxford University Hospitals
  • England
    • Birmingham, England, United Kingdom, B15 2TH
      • University Hospital Birmingham
    • Blackburn, England, United Kingdom, BB2 3HH
      • Royal Blackburn Hospital
    • Liverpool, England, United Kingdom, L7 8XP
      • Royal Liverpool University Hospital
    • London, England, United Kingdom, SE5 9RS
      • Kings College Hospital
    • London, England, United Kingdom, NW1 2BU
      • University College London
    • London, England, United Kingdom, SE1 7EH
      • Guys and St Thomas Hospital
    • Manchester, England, United Kingdom
      • Manchester Royal Infirmary
    • Manchester, England, United Kingdom, M23 9QZ
      • Wythenshawe Hospital
    • Newcastle Upon Tyne, England, United Kingdom
      • Freemans Hospital
    • Nottingham, England, United Kingdom, NG7 2UH
      • Nottingham University Hospital
    • Reading, England, United Kingdom, RG1 5AN
      • Royal Berkshire Hospital
    • Sunderland, England, United Kingdom, SR4 7TP
      • Sunderland Royal
    • Truro, England, United Kingdom, TR1 3LI
      • Royal Cornwall Hospital
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH16 4SB
      • Edinburgh Royal Infirmary
    • Glasgow, Scotland, United Kingdom, G31 2ER
      • Glasgow Royal Infirmary
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
    • Newport, Wales, United Kingdom, NP18 3XQ
      • Royal Gwent Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients with ARDS in the ICU.

Description

Inclusion Criteria:

1. Patient is receiving mechanical ventilation or high flow nasal oxygen (HFNO)
2. 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:

1. Age <18 years of age
2. More than 48 hrs after onset of ARDS
3. Receiving ECMO at the time of recruitment
4. Treatment withdrawal imminent within 24 hours
5. DNAR (Do Not Attempt Resuscitation) order (excluding advance directives) in place
6. Declined consent
7. Prisoners

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adults in the Intensive Care Setting	Diagnostic test: POC Assay; 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.

What is the study measuring?

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
Length of hospital stay	Length of hospital stay	60 days
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
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

Collaborators and Investigators

• Sponsor: Queen's University, Belfast
• Collaborators: Innovate UK; Northern Ireland Clinical Trials Unit
• Investigators: Principal Investigator: Professor D McAuley, Queens University Belfast

Publications and helpful links

General Publications

• ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2019
• Primary Completion (Actual): November 27, 2023
• Study Completion (Estimated): February 27, 2026

Study Registration Dates

• First Submitted: May 15, 2019
• First Submitted That Met QC Criteria: July 3, 2019
• First Posted (Actual): July 5, 2019

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Phenotypes; hyper and hypo-inflammatory; POC (point of care)
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Disease; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Syndrome; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
• Other Study ID Numbers: B19/06

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Following the publication of the primary and secondary outcomes there may be scope to conduct additional analyses on the data collected. In such instances formal requests for data will need to be made in writing to the CI via the Northern Ireland Clinical Trials Unit, who will discuss this with the sponsor.
• IPD Sharing Time Frame: Following the publication of the primary and secondary outcomes.
• IPD Sharing Access Criteria: Formal requests for data will need to be made in writing to the CI via the Northern Ireland Clinical Trials Unit, who will discuss this with the sponsor.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No