Clinical trial NCT05909683: Assessing the Procalcitonin-guidance and Molecular-guided Diagnosis for Therapy of Severe Infections (the MODIFY Trial)
Official title: A Randomized Prospective Clinical Trial to Assess Procalcitonin-guidance and Molecular-guided Diagnosis as Mainstay for Therapy of Severe Infections (the MODIFY Trial)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Sepsis
Keywords: Severe infections
Antibiotics
Procalcitonin
Blood Culture Identification 2 Panel (BCID2)
Reveal Rapid AST system
Lead sponsor: Hellenic Institute for the Study of Sepsis
Sponsor class: OTHER
First posted: 2023-06-18
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: According to protocol study intervention is not study drug administration; intervention includes two steps: modification of antibiotics administered; duration of antibiotic treatment. SOC patients will receive antibiotics according to standard practice of the attending physicians.

MODIFY strategy group patients will start antibiotics according to standard practice. They will be informed after randomization about the results of BCID2, Reveal Rapid AST and PCT. Physicians and investigators receiving this information are obliged to change the empirically prescribed antibiotics (escalate, de- escalate or stop) aiming to improve patient outcomes. Exceptions to overrule this algorithm will be accepted for medically unstable patients.
Primary purpose: DIAGNOSTIC

Brief summary: 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.

Detailed 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).

Eligibility criteria: 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.

Primary outcomes:
measure: The number of days under treatment with broad-spectrum antibiotics in the group receiving the MODIFY strategy compared to patients treated by standard of care.
timeFrame: Through study completion, an average of 2 years
Secondary outcomes:
measure: Time to first change of antimicrobial modification
timeFrame: Through study completion, an average of 2 years
measure: Time to the first sterile blood culture
timeFrame: Through study completion, an average of 2 years
measure: The number of patients in whom no changes in administered antibiotics will apply.
timeFrame: Through study completion, an average of 2 years
measure: At least 2-point decrease of baseline SOFA (Sequential organ failure assessment) score by day 7
timeFrame: Through study completion, an average of 2 years
measure: 28-day mortality
timeFrame: Through study completion, an average of 2 years
measure: 90-day mortality
timeFrame: Through study completion, an average of 2 years
measure: Incidence of laboratory documented Clostrioides difficile infection
timeFrame: Through study completion, an average of 2 years
measure: Length of hospital stay
timeFrame: Through study completion, an average of 2 years
measure: Cost of hospitalization
timeFrame: Through study completion, an average of 2 years
measure: Time to escalation of antibiotics
timeFrame: Through study completion, an average of 2 years
measure: Time to de-escalation of antibiotics
timeFrame: Through study completion, an average of 2 years
Other outcomes:
Locations:
city: Athens
country: Greece
facility: 2nd Propaedeutic Department of Internal Medicine, Attikon University Hospital
state: Chaidari
city: Athens
country: Greece
facility: 4th Department of Internal Medicine, Attikon University Hospital
state: Chaidari
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Elefsina "Thriasio"
state: Elefsina
city: Alexandroupolis
country: Greece
facility: 2nd Department of Internal Medicine, University General Hospital of Alexandroupolis
city: Athens
country: Greece
facility: 1st Department of Internal Medicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.
city: Athens
country: Greece
facility: 1st Department of Internal Medicine- General Hospital of Athens GENNIMATAS
city: Athens
country: Greece
facility: 3rd University Department of Internal Medicine, Sotiria Athens General Hospital
city: Athens
country: Greece
facility: 1st Department of Internal Medicine - General Hospital of Athens Sismanoglio- Amalia Fleming
city: Athens
country: Greece
facility: 3rd Department of Internal Medicine - General State Hospital of Nikaia "Saint Panteleimon" - West Attica General Hospital "Agia Varvara"
city: Piraeus
country: Greece
facility: 2nd Department of Internal Medicine, General Hospital of Piraeus "Tzaneio"
city: Thessaloníki
country: Greece
facility: 1st University Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki
city: Thessaloníki
country: Greece
facility: Intensive Care Unit, Ippokrateion General Hospital
Study officials:
affiliation: Hellenic Institute for the Study of Sepsis
name: Evangelos Giamarellos-Bourboulis, MD,PhD
role: STUDY_CHAIR
References: