Assessing the Procalcitonin-guidance and Molecular-guided Diagnosis for Therapy of Severe Infections (the MODIFY Trial)

Hellenic Institute for the Study of Sepsis

Status and phase: Active, not recruiting; Phase 3

Conditions: Sepsis

Treatments: Other: Standard of Care; Diagnostic Test: Change of antimicrobials based on BCID2 and Reveal Rapid AST tests. Stop of antimicrobials based on PCT results.

Study type: Interventional

Funder types: Other

Identifiers

NCT05909683

2022-502962-26-00 (Other Identifier)

MODIFY

Details and patient eligibility

About

MODIFY is a randomized, open-labeled, and prospective study that will be conducted in multiple Intensive Care Units (ICUs) and departments of Internal Medicine across Greece. It aims to change the traditional approach for the management of severe infections by integrating the results of BCID2, Reveal Rapid AST, and PCT, to improve patients' outcomes. Early and precise identification of the underlying causative pathogen along with the fast acquisition of the antimicrobial sensitivity results may positively impact the uncontrolled antimicrobial prescription.

Full description

Early administration of antimicrobials remains the mainstay of treatment of severe infections. The time until start of antimicrobials is so crucial that every hour of delay impacts considerably on mortality. In everyday clinical practice even when antimicrobials are administered early, it is impossible to know whether they are appropriate or not because cultures of specimens collected from the patient require at least 48 to 72 hours to provide some information about the type of pathogen and the antimicrobial susceptibilities.

BioFire ® FilmArray ® possesses four Food and Drug Administration (FDA)-cleared panels of molecular diagnosis, capable of detecting multiple targets in less than an hour of sample handling. Among them, Blood Culture Identification 2 Panel (BCID2) covers 43 targets. BCID2 provides information on the genes of resistance to antibiotics the microorganisms carry. BCID2 combined with fast AST can, however, introduce revolutionary changes in minimizing the time until the appropriate antimicrobial is prescribed. The concept of Reveal is to provide AST for a full panel of antibiotics if one Gram-negative isolate is identified in the blood flask.

Evaluation of the appropriateness of the administered therapy and decision about discontinuation or de-escalation of antimicrobials, is based on the use of biomarkers and mainly procalcitonin (PCT).

Enrollment: 190 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male or female
• For women of child-bearing potential, willingness to avoid pregnancy during the study and agreement to notify investigator if pregnancy occurs.
• Age more than or equal to 18 years
• Patients who have completed their participation in another study for more than 30 days can be included in this study.
• Written informed consent provided by the patient or by their legal representative in case of patients unable to consent due to sepsis onset affecting their mental capacity.
• Sepsis defined by the Sepsis-3 definition; this is defined separately for community-acquired sepsis and for hospital-acquired sepsis. Community-acquired sepsis is defined as any SOFA score 2 points or more for patients admitted in hospital emergencies with community-acquired pneumonia (CAP), community-acquired acute pyelonephritis (AP) or community-acquired primary bacteremia (BSI). CAP, AP and BSI are considered community-acquired for patients who have no history of hospitalization lasting more than 2 days the last 90 days or who are not under hemodialysis or who are not residents of long-term care facilities. Hospital-acquired sepsis is defined as any SOFA score increase by 2 points or more from the admission SOFA score for patients with onset of hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), acute pyelonephritis (AP) or primary bacteremia (BSI) at least 48 hours after hospital admission. For patients with history of hospitalization lasting more than 2 days the last 90 days or who are under hemodialysis or who are residents of long-term care facilities and are admitted to hospital with HAP, VAP, AP and BSI the definition of hospital-acquired sepsis applies. In this case, the baseline SOFA score is considered as the known SOFA score before infection onset.
• Presence of one of the following infections: community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), acute pyelonephritis (AP) and primary bacteremia (BSI).
• Positive blood culture

Exclusion criteria

• Failure to obtain written consent to participate
• Previous enrollment in this study within the past 90 days. Patients enrolled in another study will not be accepted.
• Patients in pregnancy or breastfeeding. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
• Patients receiving prolonged antibiotic therapies (e.g. endocarditis, implantable device-associated infection, cerebral/hepatic abscess, osteomyelitis, meningitis)
• Patients with severe infections due to viruses or parasites (e.g. Dengue, Toxoplasma gondii, Plasmodium spp.)
• Patients with infection due to Mycobacterium tuberculosis.
• Patients suffering from cystic fibrosis
• Severely immunocompromised patients such as a) patients with infection by the human immunodeficiency virus and with a CD4 count of less than 200 cells/mm3; b) neutropenic patients with less than 500 neutrophils/mm3; and c) patients with solid organ transplantation.

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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190 participants in 2 patient groups

Standard-of-care

Sham Comparator group

Description:

These patients will receive antibiotics according to standard practice of the attending physicians. The central lab will feedback to attending physicians and investigators the results of the conventional blood cultures and AST according to the routine SOP. The attending physicians and investigators will be allowed to decide for any change of antimicrobial treatment based on the results of conventional blood cultures provided to them by the central lab or any other culture provided to them by their hospital. Antibiotics will be stopped according to the local standard practice. BCID2, Reveal Rapid AST and PCT will be performed in the samples of these patients, attending physicians will not be provided such information.

Treatment:

Other: Standard of Care

MODIFY strategy

Experimental group

Description:

These patients will start antibiotics according to standard practice of the attending physicians. It is anticipated that attending physicians will be informed in maximum 5 hours after randomization about the results of BCID2 including carriage of resistance genes and of the Reveal Rapid AST in the case of Gram-negative isolates. Physicians and investigators receiving this information are obliged to change the empirically prescribed antibiotics according to the rule provided in Box 1. The attending physicians and investigators will be allowed to decide for any change of antimicrobial treatment based on the results of conventional blood cultures provided to them by the central lab or any other culture provided to them by their hospital. PCT will be measured on day 1 and then daily starting from day 5. Attending physicians will be advised to discontinue antimicrobials on the first day by day 5 when PCT value is less than 80% of the initial value or it remains below 0.5 ng/ml.

Treatment:

Diagnostic Test: Change of antimicrobials based on BCID2 and Reveal Rapid AST tests. Stop of antimicrobials based on PCT results.