suPAR to Guide Antibiotics in Emergency Department

• ClinicalTrials.gov Identifier: NCT03717350
• Recruitment Status: Recruiting
• First Posted: October 24, 2018
• Last Update Posted: July 30, 2020
• Sponsor: Hellenic Institute for the Study of Sepsis
• Information provided by (Responsible Party): Hellenic Institute for the Study of Sepsis

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Sepsis	Drug: Meropenem; Drug: Placebo	Phase 2; Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 220 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Similar appearance of study drug of both arms
• Primary Purpose: Treatment
• Official Title: A suPAR Guided Double-blind Randomized Clinical Trial of Initiation of Antibiotics for Presumed Infection at the Emergency Department
• Actual Study Start Date: October 27, 2018
• Estimated Primary Completion Date: July 31, 2021
• Estimated Study Completion Date: August 31, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; 100ml of sodium chloride 0.9% within 15 minutes intravenously	Drug: Placebo; 100ml of sodium chloride 0.9% within 15 minutes intravenously once; Other Name: Diluent
Active Comparator: Antibiotic; 2g of meropenem diluted in 100ml of sodium chloride 0.9% within 15 minutes intravenously	Drug: Meropenem; 2g of meropenem diluted in 100ml of sodium chloride 0.9% within 15 minutes intravenously administered once; Other Name: Carbapenem

Outcome Measures

Primary Outcome Measures :

1. The efficacy of the applied intervention versus standard practice on the early worsening of the patient. [ Time Frame: 1 day (24 hours) ]
   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.

Secondary Outcome Measures :

1. Sepsis mortality [ Time Frame: 28 days ]
   Comparative efficacy of the applied intervention on mortality for patients meeting the Sepsis-3 definition of sepsis
2. Short-term mortality [ Time Frame: 7 days ]
   Comparative efficacy of the applied intervention on 7-day mortality
3. Long-term mortality 1 [ Time Frame: 60 days ]
   Comparative efficacy of the applied intervention on 60-day mortality
4. Long-term mortality 2 [ Time Frame: 90 days ]
   Comparative efficacy of the applied intervention on 90-day mortality
5. Infection resolution [ Time Frame: 90 days ]
   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.
6. Change of initial treatment [ Time Frame: 28 days ]
   Comparative efficacy of the applied intervention on the need to change antibiotics
7. Duration of hospitalization [ Time Frame: 90 days ]
   Comparative efficacy of the applied intervention on the duration of hospitalization
8. Rate of new infections [ Time Frame: 90 days ]
   Comparative efficacy of the applied intervention on the rate of new infections
9. The early worsening of the patient [ Time Frame: 1 day (24 hours) ]
   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Written informed consent provided by the patient or by their legal representative in case of patients unable to consent
2. Age equal to or above 18 years
3. Male or female gender
4. Clinical suspicion of infection
5. qSOFA equal to 1 point
6. suPAR blood level equal or above 12 ng/ml

Exclusion Criteria:

1. Denial to consent
2. Patients with 2 or 3 qSOFA signs
3. Pregnancy (confirmed by blood or urinary pregnancy test) for female patients of reproductive age
4. Organ transplantation
5. Fully-blown sepsis with overt failing organs necessitating immediate resuscitation as defined by the attending physicians
6. Do not resuscitate decision

Contacts and Locations

Contacts

Contact: Evangelos J Giamarellos-Bourboulis, MD, PhD; +306945521800; egiamarel@med.uoa.gr

Contact: Charambos Gogos, MD, PhD; +306944799784; egogos@med.upatras.gr

Locations

Greece

4th Department of Internal Medicine, ATTIKON University Hospital; Recruiting

Athens, Attiki, Greece, 12462

Contact: Antonios Papadopoulos, MD, PhD +306977302400 antpapa1@otenet.gr

Contact: Evdoxia Kyriazopoulou, MD, PhD +302105832563 ekyr@med.uoa.gr

Sub-Investigator: Antonios Papadopoulos, MD, PhD

Sub-Investigator: Nikolaos Antonakos, MD, PhD

Sub-Investigator: Maria-Evangelia Adami, MD

1st Department of Internal Medicine of G. GENNIMATAS General Hospital; Recruiting

Athens, Greece, 11527

Contact: George Adamis, MD 2107768534 adamismd@otenet.gr

3rd Department of Internal Medicine at SOTIRIA General Hospital of Chest Diseases of Athens; Recruiting

Athens, Greece, 11527

Contact: Garyfallia Poulakou, MD, PhD 2107763400 gpoulakou@gmail.com

Εmergency Department of Sismanogleion Athens General Hospital; Recruiting

Athens, Greece, 15126

Contact: Vassileios Kaldis, MD 2132058 841 vkaldis@yahoo.gr

Department of Internal Medicine, Patras University Hospital; Recruiting

Patras, Greece

Contact: Charalambos Gogos, MD, PhD +306944799784 cgogos@med.upatras.gr

Contact: Karolina Akinosoglou, MD, PhD ++306977762897 akin@upatras.gr

Principal Investigator: Charalambos Gogos, MD, PhD

Sub-Investigator: Karolina Akinosoglou, MD, PhD

Sub-Investigator: Ann-Liz Delastic, MD, PhD

Sponsors and Collaborators

Hellenic Institute for the Study of Sepsis

Investigators

• Study Chair: Evangelos Giamarellos-Bourboulis, MD, PhD; Attikon Hospital

More Information

Publications:

Giamarellos-Bourboulis EJ, Tsaganos T, Tsangaris I, Lada M, Routsi C, Sinapidis D, Koupetori M, Bristianou M, Adamis G, Mandragos K, Dalekos GN, Kritselis I, Giannikopoulos G, Koutelidakis I, Pavlaki M, Antoniadou E, Vlachogiannis G, Koulouras V, Prekates A, Dimopoulos G, Koutsoukou A, Pnevmatikos I, Ioakeimidou A, Kotanidou A, Orfanos SE, Armaganidis A, Gogos C; Hellenic Sepsis Study Group. Validation of the new Sepsis-3 definitions: proposal for improvement in early risk identification. Clin Microbiol Infect. 2017 Feb;23(2):104-109. doi: 10.1016/j.cmi.2016.11.003. Epub 2016 Nov 14.

Giamarellos-Bourboulis EJ, Norrby-Teglund A, Mylona V, Savva A, Tsangaris I, Dimopoulou I, Mouktaroudi M, Raftogiannis M, Georgitsi M, Linnér A, Adamis G, Antonopoulou A, Apostolidou E, Chrisofos M, Katsenos C, Koutelidakis I, Kotzampassi K, Koratzanis G, Koupetori M, Kritselis I, Lymberopoulou K, Mandragos K, Marioli A, Sundén-Cullberg J, Mega A, Prekates A, Routsi C, Gogos C, Treutiger CJ, Armaganidis A, Dimopoulos G. Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor. Crit Care. 2012 Aug 8;16(4):R149. doi: 10.1186/cc11463.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Kyriazopoulou E, Poulakou G, Giamarellos-Bourboulis EJ. Biomarkers in sepsis: can they help improve patient outcome? Curr Opin Infect Dis. 2021 Apr 1;34(2):126-134. doi: 10.1097/QCO.0000000000000707. Review.

• Responsible Party: Hellenic Institute for the Study of Sepsis
• ClinicalTrials.gov Identifier: NCT03717350
• Other Study ID Numbers: SUPERIOR
• First Posted: October 24, 2018
• Last Update Posted: July 30, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hellenic Institute for the Study of Sepsis:

biomarkers; suPAR; outcome; antibiotics

Additional relevant MeSH terms:

Emergencies; Disease Attributes; Pathologic Processes; Meropenem; Anti-Bacterial Agents; Anti-Infective Agents