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

Acute Respiratory Distress Syndrome (ARDS) Clinical Trial

— PHIND  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04009330
• Other study ID #: B19/06
• Status: Active, not recruiting
• Start date: November 22, 2019
• Est. completion date: February 27, 2026

Study information

• Verified date: February 2024
• Source: Queen's University, Belfast
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 480
• Est. completion date: February 27, 2026
• Est. primary completion date: November 27, 2023
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lung Injury
• Acute Respiratory Distress Syndrome (ARDS)
• Respiratory Distress Syndrome
• Respiratory Distress Syndrome, Newborn
• Syndrome

Intervention

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.

Locations

Country	Name	City	State
Ireland	St Vincents Hospital	Dublin
United Kingdom	Royal Victoria Hospital	Belfast
United Kingdom	Birmingham Heartlands Hospital	Birmingham
United Kingdom	University Hospital Birmingham	Birmingham	England
United Kingdom	Royal Blackburn Hospital	Blackburn	England
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	Edinburgh Royal Infirmary	Edinburgh	Scotland
United Kingdom	Glasgow Royal Infirmary	Glasgow	Scotland
United Kingdom	Royal Liverpool University Hospital	Liverpool	England
United Kingdom	Guys and St Thomas Hospital	London	England
United Kingdom	Imperial College London	London
United Kingdom	Kings College Hospital	London	England
United Kingdom	University College London	London	England
United Kingdom	Manchester Royal Infirmary	Manchester	England
United Kingdom	Wythenshawe Hospital	Manchester	England
United Kingdom	Freemans Hospital	Newcastle Upon Tyne	England
United Kingdom	Royal Gwent Hospital	Newport	Wales
United Kingdom	Nottingham University Hospital	Nottingham	England
United Kingdom	Oxford University Hospitals	Oxford
United Kingdom	Royal Berkshire Hospital	Reading	England
United Kingdom	Sunderland Royal	Sunderland	England
United Kingdom	Royal Cornwall Hospital	Truro	England

Sponsors (3)

Lead Sponsor	Collaborator
Queen's University, Belfast	Innovate UK, Northern Ireland Clinical Trials Unit

Countries where clinical trial is conducted

Ireland,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Difference in time to extubation	Difference in time to extubation	60 days
Secondary	Intubation rate in patients on HFNO	Intubation rate in patients on HFNO	60 days
Secondary	Reintubation Rate	Reintubation Rate	60 days
Secondary	Number of ventilator free days at day 28	Number of ventilator free days at day 28	28 days
Secondary	Number of days on ventilation	Number of days on ventilation	60 days
Secondary	Length of ICU stay	Length of ICU stay	60 days
Secondary	Length of hospital stay	Length of hospital stay	60 days
Secondary	Mortality at day 28	Mortality at day 28	28 days
Secondary	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
Secondary	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
Secondary	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
Secondary	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