Clinical trial NCT04009330: Clinical Evaluation of a Point of Care (POC) Assay to Identify Phenotypes in the Acute Respiratory Distress Syndrome
Official title: Clinical Evaluation of a POC Assay to Identify Phenotypes in the Acute Respiratory Distress Syndrome
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Acute Respiratory Distress Syndrome (ARDS)
Keywords: hyper and hypo-inflammatory
Phenotypes
POC (point of care)
Lead sponsor: Queen's University, Belfast
Sponsor class: OTHER
Collaborators: name: Northern Ireland Clinical Trials Unit
name: Innovate UK
First posted: 2019-07-05
Enrollment: 480
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with ARDS in the ICU.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: The primary outcome is mortality at 60 days in the hyper-inflammatory and hypo-inflammatory phenotypes in patients with ARDS.
timeFrame: 60 days
Secondary outcomes:
measure: Difference in time to extubation
timeFrame: 60 days
measure: Intubation rate in patients on HFNO
timeFrame: 60 days
measure: Reintubation Rate
timeFrame: 60 days
measure: Number of ventilator free days at day 28
timeFrame: 28 days
measure: Number of days on ventilation
timeFrame: 60 days
measure: Length of ICU stay
timeFrame: 60 days
measure: Length of hospital stay
timeFrame: 60 days
measure: Mortality at day 28
timeFrame: 28 days
measure: Agreement of phenotype classification using a POC assay and standard laboratory based assays.
timeFrame: Day 1 and day 3
measure: Agreement of phenotype classification using a POC assay and the clinical study dataset.
timeFrame: 2 Years
measure: Agreement of phenotype classification between day 1 and day 3.
timeFrame: Day 1 and Day 3
measure: Frequency of assay technical failure rate will be used to determine the feasibility of delivering a POC assay in NHS intensive care setting.
timeFrame: 2 years
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: St Vincents Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
state: England
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: University College London
state: England
city: London
country: United Kingdom
facility: Guys and St Thomas Hospital
state: England
city: London
country: United Kingdom
facility: Kings College Hospital
state: England
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
state: England
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
state: England
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freemans Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
state: England
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
state: England
city: Sunderland
country: United Kingdom
facility: Sunderland Royal
state: England
city: Truro
country: United Kingdom
facility: Royal Cornwall Hospital
state: England
city: Edinburgh
country: United Kingdom
facility: Edinburgh Royal Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: Scotland
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
city: Newport
country: United Kingdom
facility: Royal Gwent Hospital
state: Wales
city: Belfast
country: United Kingdom
facility: Royal Victoria Hospital
city: Birmingham
country: United Kingdom
facility: Birmingham Heartlands Hospital
city: London
country: United Kingdom
facility: Imperial College London
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals
Study officials:
affiliation: Queens University Belfast
name: Professor D McAuley
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.