THE ROLE OF PANCREATIC STONE PROTEIN (PSP) AND PSP-GUIDED EARLY MEROPENEM TREATMENT TO MITIGATE SEPSIS RISK AT THE EMERGENCY DEPARTMENT: THE PROMISE DOUBLE BLIND, PHASE III, RANDOMIZED CONTROLLED CLINICAL TRIAL

THE ROLE OF PANCREATIC STONE PROTEIN (PSP) AND PSP-GUIDED EARLY MEROPENEM TREATMENT TO MITIGATE SEPSIS RISK AT THE EMERGENCY DEPARTMENT: THE PROMISE DOUBLE BLIND, PHASE III, RANDOMIZED CONTROLLED CLINICAL TRIAL

The goal of this clinical trial is to demonstrate the clinical benefit of early intervention with meropenem in adult patients of both sexes with suspected infection and risk of sepsis. The primary objective is to evaluate the clinical benefit of a protein called Pancreatic Stone Protein (PSP), which, if elevated, indicates that patient may be at increased risk of developing sepsis. The secondary objectives are to investigate the impact of early antibiotic treatment with meropenem on progression to sepsis, survival and mortality. Researchers will compare meropenem to a placebo (a look-alike substance that contains no drug).

Participants will:

• Take a single dose of meropenem or a placebo
• Be evaluated at designated timepoints post administration until their discharge and, also, on days 28 and 90 post administration, respectively.

Sepsis is among the leading causes of death worldwide. It is well-perceived that early start of antibiotics is the mainstay of management. According to the Surviving Sepsis Campaign guidelines, early resuscitation with antibiotics should start in all patients with suspected infection and clinical features suggestive of sepsis. Current clinical assessment tools, including the quick Sequential Organ Failure Assessment (qSOFA) and the National Early Warning Score 2 (NEWS2), are useful for identifying patients at increased risk of adverse outcomes. However, patients who do not meet criteria for overt sepsis or have only limited clinical abnormalities may still be at substantial risk of unfavorable outcome. Biomarkers may provide additional information for the early identification of such patients and may allow targeted intervention before the development of clinically overt organ dysfunction.

Patients with only one qSOFA sign, and even some patients with nil criteria of qSOFA, may still be at risk of unfavorable outcomes. Previous analyses from the Hellenic Sepsis Study Group showed that patients with one qSOFA sign and elevated soluble urokinase plasminogen activator receptor (suPAR) blood levels had a risk of 28-day mortality similar to that of patients with qSOFA of 2 or more. In the randomized controlled SUPERIOR trial, patients identified by one qSOFA sign and elevated suPAR were randomized to receive a single dose of meropenem or placebo. Early meropenem treatment resulted in a 74% relative reduction in early worsening of the clinical state, defined as at least a 1-point increase in the total SOFA score from baseline. These findings support the concept of using biomarkers together with clinical assessment to identify patients with suspected infection who may benefit from early antimicrobial intervention.

Pancreatic Stone Protein (PSP), also known as Regenerating Protein 1A (Reg1A), is a 16-kDa C-type lectin-like glycoprotein predominantly secreted by pancreatic acinar cells and, also, expressed in other tissues, including gastric and intestinal epithelium. PSP is involved in tissue regeneration and in systemic stress and immune responses. Through its ability to bind and aggregate bacteria and activate neutrophils, PSP has been proposed as a biomarker of systemic inflammation and infection. Previous clinical studies have demonstrated increased PSP concentrations in patients with sepsis compared with patients with organ dysfunction unrelated to infection. PSP may increase earlier than conventional inflammatory biomarkers, including C-reactive protein and procalcitonin, and may therefore have a role in the early identification of patients at risk of sepsis and clinical deterioration.

The PROMPT study, which took place at the Emergency Departments (ED) of six hospitals in Greece, evaluated PSP in patients admitted with suspected infection, defined by the presence of fever, hypothermia, or tachycardia. PSP concentrations were retrospectively measured in stored blood samples using the IVD CAPSULE PSP assay on the abioSCOPE device. This post-hoc analysis showed that the combination of PSP ≥300 ng/mL with one sign of qSOFA and/or a NEWS2 score of 5 or 6 had a sensitivity of more than 30% and a specificity of more than 90% for the detection of sepsis. The diagnostic performance of this combination was similar to that of qSOFA ≥2. These findings support the use of PSP in combination with clinical assessment to identify patients with suspected infection who may be at increased risk of sepsis, including patients who do not have sufficient clinical abnormalities to meet higher-risk qSOFA criteria.

Early antimicrobial treatment is a cornerstone of the management of patients with suspected bacterial infection and sepsis. Meropenem is a broad-spectrum antibacterial agent with activity against a wide range of clinically relevant pathogens and is an established treatment option for severe bacterial infections. The selection of meropenem for the PROMISE trial is supported by promising results of the SUPERIOR trial in which patients with suspected infection at risk of death. The dose selected for PROMISE remains within the scope of the approved dosing recommendations for hospitalized patients who may require continued antibiotic treatment. Administration of a single study dose therefore does not impose any restriction on subsequent antimicrobial management.

The PROMISE trial is designed to demonstrate how early intervention with meropenem single dose in patients with suspicion of infection at risk of death may improve outcome. PROMISE is a multicenter, double-blind, placebo-randomized, Phase III controlled clinical trial that will be conducted in the EDs of 10 hospitals in Greece.

Adult patients presenting to the ED with suspicion of infection will undergo screening at triage. Eligible patients will be those with suspected infection, defined by the presence of at least one clinical feature suggestive of infection, together with either one sign of qSOFA or a NEWS2 score of 5 or 6, and a PSP concentration of at least 300 ng/mL. Written informed consent will be obtained before enrolment. For patients who are unable to provide informed consent, consent may be provided by a first-degree relative in accordance with the applicable ethical and regulatory requirements.

Suspicion of infection will be defined by the presence of at least one of the following: core body temperature of at least 38°C, heart rate greater than 90 beats/ min, acute shortness of breath, dysuria, diarrhea, abdominal pain, or other complaints that, according to the investigator's clinical judgment, indicate or are correlated with the presence of infection. The PROMISE population specifically targets patients who demonstrate an intermediate level of clinical risk. Eligible participants may have one qSOFA sign, including mental confusion, systolic blood pressure below 100 mmHg, or respiratory rate greater than 22 breaths/min. Alternatively, patients with no qSOFA signs may be eligible when their NEWS2 score is 5 or 6.

Patients with two or three qSOFA signs, NEWS2 of 7 or greater, or established severe clinical deterioration requiring high-flow oxygen, mechanical ventilation, or vasopressor support will not be eligible for the trial. Patients will also be excluded if they are younger than 18 years, decline informed consent, are pregnant or lactating, have known hypersensitivity to meropenem or to any other antibacterial agent that includes meropenem, have severe hypersensitivity to any antibacterial agent belonging to beta lactam class (eg. penicillins or cephalosporins) or receiving medication clinical inappropriate within the study context, including probenecid, valproic acid, or warfarin. Patients with documented acute organ dysfunction compatible with sepsis, reflected by an increase in SOFA-2 score of at least 2 points, will also be excluded.

Patients meeting the eligibility criteria will be randomized to receive either a single dose of meropenem or placebo. The study treatment will be administered at an early stage of the patient's ED evaluation following identification of the predefined clinical and biomarker profile. The trial is double-blinded, such that treatment allocation will remain concealed during the randomized treatment phase.

Inclusion Criteria:

• Written informed consent
• Adult (≥18 years) patients of both sexes
• Infection suspicion defined as the presence of at least one of: i) fever ≥38°C; ii) tachycardia (>90 beats/min); iii) acute presence of shortness of breath or dysuria, or diarrhea or abdominal pain; and iv) complaints that according to investigator's discretion indicate/are correlated with the presence of infection
• Presence of only one of qSOFA signs (mental confusion, systolic blood pressure less than 100mmHg, respiratory rate more than 22 breaths/min) OR NEWS2 equal to 5 or 6. It is explicitly stated that patients with 0 qSOFA signs may be enrolled in the study if the NEWS2 is 5 or 6. It is also explicitly stated that patients with NEWS2 less than 5 may be enrolled in the study if qSOFA is equal to one.
• PSP ≥300 ng/ml measured at the Triage

Exclusion Criteria:

• Deny to consent
• Age less than 18 years
• Presence of nil, two or three signs of qSOFA
• NEWS2 ≥7
• Full-blown sepsis with overt organ dysfunction (defined as need of high flow oxygen or mechanical ventilation or vasopressors)
• Pregnancy (pregnancy test either blood or uninary will be conducted at the ED for female patients of reproductive age) or lactation
• Hypersensitivity to meropenem, or to any other antibacterial agent that includes meropenem. Severe hypersensitivity to any antibacterial agent belonging to beta lactam class (eg. penicillins or cephalosporins).
• Patients receiving probenecid, valproic acid or warfarin.
• Documented acute organ dysfunction compatible with sepsis, as reflected by an increase in SOFA-2 score by ≥2 points.