TRAITS

What is a treatable trait?

We define treatable traits as measurable biological abnormalities, that are proximate determinants of clinical outcomes (e.g., organ dysfunction or death), and are modifiable with interventions. Our concept is that such treatable traits in critically ill adults are syndrome agnostic i.e., same treatable trait can be found different critical illness syndromes such as sepsis, and acute respiratory distress syndrome.

TRAITS Programme consists of 

1. Platform randomised clinical trial
2. Embedded biological characterisation

Traits and interventions

Differences between patients (loosely termed heterogeneity) is the norm during critical illness. Factors that predispose to critical illness vary from genetic predisposition, comorbidities, through to socioeconomic, and environmental factors. The inciting insult or trigger for critical illness can vary; the common aetiologies include infection, trauma, and other acute inflammatory illnesses such as pancreatitis and autoimmune diseases.

Whilst the inciting insults for critical illness vary, these disparate insults share many dysregulated canonical host immune responses characterised by concurrently increased inflammatory and anti-inflammatory innate immune responses, with a relative suppression of adaptive immunity early on in critical illness. These shared dysregulated canonical host immune response patterns are apparent immediately after trauma, after endotoxin challenge, after surgery, in illnesses like pancreatitis, ARDS, and sepsis. These responses often result in a complicated illness trajectory with either early deaths, or prolonged organ dysfunction and late mortality, often with secondary infections or reactivation of dormant herpes viruses. Importantly, patient outcomes are determined mainly by the nature and magnitude of these host responses. The reason being host responses to insult or injury results in global reprioritization in >80% of the cellular functions and pathways.  

Fundamental biological observations described above led us to propose the treatable trait hypothesis, which is explored in the TRAITS trial, that focuses on modifiable biological pathways that are syndrome agnostic. 

Treatable traits are biological abnormalities arising because of the insult/injury causing critical illness that are:  

1. syndrome agnostic  
2. measurable with feasible biomarkers or surrogates 
3. impact patient outcomes (i.e., in causal pathway to or deterministic of outcome), and  
4. are modifiable or reversible with intervention.  

It is important to highlight that in the TRAITS trial, we plan to evaluate only those interventions with either early or late phase RCT data in critically ill patients, with evidence for safety, with evidence of favourable biological effects when administered, and are not currently part of usual care. Examples include immunoglobulins, recombinant interleukin-7, check point molecule blockers, and immunomodulatory agents (such as glucocorticoids, interleukin-6 antagonists, imatinib, baricitinib, granulocyte-monocyte colony stimulating factors). 

Traits

We currently have the following treatable traits selected.    

1. LYMP-RESP: Patients with clinical evidence of lymphopenia and respiratory dysfunction  
2. ENDO-SHOCK: Patients with clinical evidence of shock and inflammation  

Our treatable traits are further defined within the trial protocols – each treatable trait group has clear eligibility criteria ensuring patients can be enrolled to the correct trait group. 

Interventions

Our approach enables comparison of multiple interventions to a single control (usual care) with a treatable trait-specific protocol (TSP).  The minimum number of interventions within one TSP is two, with one of them being usual care and the maximum number is limited only by statistical power.  Of note, the addition of any new interventions and/or traits will be subject to ethical and regulatory approval prior to initiation. 

The current interventions are shown below.