suPAR to Guide Antibiotics in Emergency Department

Study Overview
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Brief Summary
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The aim of the current study is to evaluate suPAR - guided medical intervention, consisting of early antibiotic administration at the emergency room for presumed infection and sepsis and evaluate the impact of this intervention to the patients' final outcome. Since the traditionally used biomarkers (PCT, CRP) and scores (SOFA score) for early recognition of severity of infection fail to achieve maximum accuracy in all cases, suPAR levels are assessed as a probably better prognostic rule for early recognition of severe infections. The primary study endpoint will be the comparative efficacy of the early suPAR-guided administration of antibiotics versus standard practice on 28-day mortality.

Detailed Description
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Sepsis is among the leading causes of death worldwide. It is well-perceived that early recognition of sepsis is the mainstay of treatment. Recently it has been proposed that the quick sequential organ fialure assessment (qSOFA) score can be used as a screening tool in the emergency department (ED) to triage patients with high-risk of death; patients scoring positive at least two of the three signs of qSOFA are at a high-risk for death. However, this is challenged since it may be the case that the risk of death is high even among patients with only one sign of qSOFA. Soluble urokinase plasminogen activator receptor (suPAR), the soluble form of the membrane bound receptor (uPAR), is a recently known glycoprotein involved in inflammation. uPAR is expressed on various immune cells (neutrophils, lymphocytes, monocytes, macrophages) and is cleaved from their surface after an inflammatory stimuli to enhance chemotaxis and cell migration. Increased suPAR blood levels mirror the degree of activation of the immune system by different antigenic stimuli including diverse neoplastic and infectious agents and other inflammation-mediated diseases. SuPAR levels generally correlate to the severity of the disease. It has been shown that suPAR blood levels have low diagnostic value (cannot discriminate between bacterial, viral or parasitic infection, Gram (+) or Gram (-) bacteraemia. However, they present superior prognostic value as compared with single parameters of inflammation and organ dysfunction (like C-reactive protein (CRP) and procalcitonin (PCT) in critically ill patients, and suPAR's prognostic value of death is even more enhanced when combined to other biomarkers and physiological scores (e.g. Acute Physiology and Chronic Health Evaluation-APACHE II). Why choose suPAR as biomarker at emergency basis? Because, in contrast to many pro-inflammatory cytokines, suPAR exhibits favorable properties due to its high stability in serum samples and limited circadian changes in plasma concentrations. It also constitutes a serum/plasma biomarker that is easily performed on-site and provides information within one hour after sampling21, 22. Unpublished data of the Hellenic Sepsis Study Group (HSSG) suggest that among patients with at least one sign of the qSOFA score, those with suPAR greater than 12 ng/ml are at a substantial risk for death with mortality exceeding 30%. To this end, patients with suspicion for an infection and with qSOFA 1 and suPAR greater than 12 ng/ml constitute a group of patients requiring early intervention. The aim of the current study is to evaluate suPAR - guided medical intervention, consisting of early antibiotics' administration at the emergency room for presumed infection and sepsis and evaluate the impact of this intervention to the patients' final outcome.

Official Title
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A suPAR Guided Double-blind Randomized Clinical Trial of Initiation of Antibiotics for Presumed Infection at the Emergency Department

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Meropenem
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent provided by the patient or by their legal representative in case of patients unable to consent Age equal to or above 18 years Male or female gender Clinical suspicion of infection qSOFA equal to 1 point suPAR blood level equal or above 12 ng/ml Exclusion Criteria: Denial to consent Patients with 2 or 3 qSOFA signs Pregnancy (confirmed by blood or urinary pregnancy test) for female patients of reproductive age Organ transplantation Fully-blown sepsis with overt failing organs necessitating immediate resuscitation as defined by the attending physicians Do not resuscitate decision

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>100ml of sodium chloride 0.9% within 15 minutes intravenously | Drug: Placebo<br>* 100ml of sodium chloride 0.9% within 15 minutes intravenously once<br>* Other names: Diluent;|
| Active Comparator: Antibiotic<br>2g of meropenem diluted in 100ml of sodium chloride 0.9% within 15 minutes intravenously | Drug: Meropenem<br>* 2g of meropenem diluted in 100ml of sodium chloride 0.9% within 15 minutes intravenously administered once<br>* Other names: Carbapenem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The efficacy of the applied intervention versus standard practice on the early worsening of the patient. | The primary study endpoint will be the comparative efficacy of the applied intervention (meropenem versus standard practice on the early worsening of the patient. This is defined as any at least one point increase of the admission total SOFA score the first 24 hours. | 1 day (24 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sepsis mortality | Comparative efficacy of the applied intervention on mortality for patients meeting the Sepsis-3 definition of sepsis | 28 days | 
| Short-term mortality | Comparative efficacy of the applied intervention on 7-day mortality | 7 days | 
| Long-term mortality 1 | Comparative efficacy of the applied intervention on 60-day mortality | 60 days | 
| Long-term mortality 2 | Comparative efficacy of the applied intervention on 90-day mortality | 90 days | 
| Infection resolution | Effect of the intervention on the time to infection resolution. This time point is limited for patients who will eventually be diagnosed of a specific infectious diseases making them eligible for the study and it is defined as the time point when all clinical signs of the infection are cleared. | 90 days | 
| Change of initial treatment | Comparative efficacy of the applied intervention on the need to change antibiotics | 28 days | 
| Duration of hospitalization | Comparative efficacy of the applied intervention on the duration of hospitalization | 90 days | 
| Rate of new infections | Comparative efficacy of the applied intervention on the rate of new infections | 90 days | 
| The early worsening of the patient | The early worsening of the patient defined as for the primary endpoint but analyzed separately per quartile of the total SOFA score of the patient population | 1 day (24 hours) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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biomarkers, suPAR, outcome, antibiotics