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

Sepsis Clinical Trial

— MODIFY  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05909683
• Other study ID #: MODIFY
• Secondary ID: 2022-502962-26-0
• Status: Recruiting
• Phase: Phase 3
• Start date: September 14, 2023
• Est. completion date: July 25, 2025

Study information

• Verified date: December 2023
• Source: Hellenic Institute for the Study of Sepsis
• Contact: Evangelos Giamarellos-Bourboulis, MD,PhD
• Phone: 00302105831994
• Email: egiamarel[@]med.uoa.gr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: July 25, 2025
• Est. primary completion date: July 25, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Infections
• Sepsis

Intervention

Diagnostic Test:
• Change of antimicrobials based on BCID2 and Reveal Rapid AST tests. Stop of antimicrobials based on PCT results.
After the patient's blood flask is flagged positive for bloodstream infection, the blood sample will be assessed in the BCID2 diagnostic test in order to identify the underlying pathogens the patient is infected with. After the identification, and in the presence of gram-negative bacteria, the sample will be assessed in the Reveal Rapid AST test to provide information about which antimicrobials the specific pathogens are sensitive to. When both the identification of the pathogen and the sensitivities are available, the central laboratory will inform the attending physicians, who are obliged to change the standard of care antimicrobial therapy administered based on the rule in Box1 of the protocol. Finally, based on the results of the procalcitonin (PCT) 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, the attending physicians should discontinue the antimicrobial therapy.

Other:
• Standard of Care
Standard of care practices of the specific study site. Antimicrobials will be administered based on the attending physicians' critical opinion, and discontinuation will be done based on the standard procedures of the study site.

Locations

Country	Name	City	State
Greece	2nd Department of Internal Medicine, University General Hospital of Alexandroupolis	Alexandroupolis
Greece	1st Department of Internal Medicine - General Hospital of Athens Sismanoglio- Amalia Fleming	Athens
Greece	1st Department of Internal Medicine, General Hospital of Athens KORGIALENIO-BENAKIO E.E.S.	Athens
Greece	1st Department of Internal Medicine, General Hospital of Elefsina "Thriasio"	Athens	Elefsina
Greece	1st Department of Internal Medicine- General Hospital of Athens GENNIMATAS	Athens
Greece	2nd Propaedeutic Department of Internal Medicine, Attikon University Hospital	Athens	Chaidari
Greece	3rd Department of Internal Medicine - General State Hospital of Nikaia "Saint Panteleimon" - West Attica General Hospital "Agia Varvara"	Athens
Greece	3rd University Department of Internal Medicine, Sotiria Athens General Hospital	Athens
Greece	4th Department of Internal Medicine, Attikon University Hospital	Athens	Chaidari
Greece	2nd Department of Internal Medicine, General Hospital of Piraeus "Tzaneio"	Piraeus
Greece	1st University Department of Internal Medicine, AHEPA University General Hospital of Thessaloniki	Thessaloníki
Greece	Intensive Care Unit, Ippokrateion General Hospital	Thessaloníki

Sponsors (1)

Lead Sponsor	Collaborator
Hellenic Institute for the Study of Sepsis

Country where clinical trial is conducted

Greece, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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.	Through study completion, an average of 2 years
Secondary	Time to first change of antimicrobial modification	Time to first change of antimicrobial modification	Through study completion, an average of 2 years
Secondary	Time to the first sterile blood culture	Time to the first sterile blood culture	Through study completion, an average of 2 years
Secondary	The number of patients in whom no changes in administered antibiotics will apply.	The number of patients in whom no changes in administered antibiotics will apply.	Through study completion, an average of 2 years
Secondary	At least 2-point decrease of baseline SOFA (Sequential organ failure assessment) score by day 7	At least 2-point decrease of baseline SOFA (Sequential organ failure assessment) score by day 7. SOFA ranges between 0-24 and the higher the score, the worst the outocome of the patient.	Through study completion, an average of 2 years
Secondary	28-day mortality	28-day mortality	Through study completion, an average of 2 years
Secondary	90-day mortality	90-day mortality	Through study completion, an average of 2 years
Secondary	Incidence of laboratory documented Clostrioides difficile infection	Incidence of laboratory documented Clostrioides difficile infection	Through study completion, an average of 2 years
Secondary	Length of hospital stay	Length of hospital stay	Through study completion, an average of 2 years
Secondary	Cost of hospitalization	Cost of hospitalization	Through study completion, an average of 2 years
Secondary	Time to escalation of antibiotics	Time to escalation of antibiotics	Through study completion, an average of 2 years
Secondary	Time to de-escalation of antibiotics	Time to de-escalation of antibiotics	Through study completion, an average of 2 years