A Clinical Trial of Procalcitonin-guided Antimicrobial Therapy in Sepsis (PROGRESS)

A Randomized Prospective Clinical Trial to Assess the Role of Procalcitonin-guided Antimicrobial Therapy to Reduce Long-term Infections Sequelae

The aim of the study is to demonstrate if using one procalcitonin (PCT)-guided rule of stop of antimicrobials, the incidence of infections by C.difficile and by Multi-Drug-Resistant (MDR) bacteria during the next six months may be significantly decreased.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Diagnostic test: Procalcitonin measurement

Detailed Description

Early administration of antimicrobials remains the mainstay of treatment of severe infections. Current guidelines of management of severe sepsis suggest that initial therapy of a patient should be reviewed after 48 to 72 hours. At that stage some patients are doing well, whereas others fail to respond. When microbiology cultures of biological specimens fail to provide information for the microbial cause of an infection and susceptibilities to antimicrobials, antimicrobial stewardship relies on the use of biomarkers and mainly procalcitonin (PCT). Data so far, suggest that early changes of serum PCT can inform about the prognosis of the septic patient, with greater values reflecting a worse outcome and higher mortality and that serial measurements within 48-72 hours provide adequate information of the appropriateness of the administered antimicrobials. Moreover the use of a procalcitonin guided-treatment in surgical as well as in non-surgical critically-ill patients, is seen to be non-inferior to the standard antibiotic approach and leads to a shorter antibiotic exposure, having possible beneficial effect on reducing microbial resistance and therapy costs.

In the largest study conducted so far, de Jong et al showed that PCT-guided stop of treatment was not only safe compared with standard of care antibiotic duration, but also led to a better outcome i.e. significant decrease of both 28-day and 1-year mortality. The results of this study are a major contribution in the field of critical care since they prove for the first time that PCT guidance of antimicrobial treatment allows not only proper antimicrobial stewardship but it is also associated with survival benefit. However, de Jong et al did not provide findings to explain the underlying mechanism of survival benefit. As a rule critically ill patients run two major risks coming from the long-term administration of antimicrobials; the first is infections by Clostridium difficile coming from the ecological damage of gut flora and the second is the risk of infections by multidrug-resistant (MDR) bacteria colonizing the gut. MDR is emerging after the ecological pressure of broad-spectrum antimicrobial usually administered to the critically ill patient.

• Study Type: Interventional
• Enrollment (Actual): 266
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 12462
    • 4th Department of Internal Medicine, Attikon University Hospital
  • Athens, Greece, 11527
    • 1st Department of Internal Medicine, General Hospital of Athens "G. Gennimatas"
  • Athens, Greece, 11527
    • 3rd Department of Internal Medicine, Sotiria Athens General Hospital
  • Athens, Greece, 15126
    • 2nd Department of internal Medicine, General Hospital of Attiki "Sismanogleio"
  • Athens, Greece, 19600
    • 1st Department of Internal Medicine, General Hospital of Elefsina "Thriasio"
  • Athens, Greece, 19600
    • 2nd Department of Internal Medicine, General Hospital of Elefsina "Thriasio"
  • Piraeus, Greece, 18536
    • 2nd Department of Internal Medicine, General Hospital of Piraeus "Tzaneio"

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Male or female
• In case of women, unwillingness to remain pregnant during the study period.
• Age more than or equal to 18 years
• Sequential Organ Failure Assessment (SOFA) score more than or equal to 2 points for patients admitted in the emergencies and with a more than or equal to a 2-point increase of admission SOFA score for hospitalized patients.
• Presence of one of the following infections: community-acquired pneumonia, hospital-acquired pneumonia, ventilator-associated pneumonia, bacteremia and acute pyelonephritis. Any infection with onset more than 48 hours post hospital admission is considered one hospital-acquired infection.

Exclusion Criteria:

• Failure to obtain written consent to participate
• 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 infected with Mycobacterium tuberculosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PCT group; Procalcitonin measurement and Discontinuation of antimicrobials according to Procalcitonin kinetics	Diagnostic test: Procalcitonin measurement; Discontinuation of antimicrobials according to Procalcitonin Kinetics
No Intervention: Standard of care; Standard practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change of infection-associated adverse events rate. The infection-associated adverse events rate are any case of Clostridium Difficile Infection (CDI) or infection by MDR or infection-related death.	The change of infection-associated adverse events rate. The infection-associated adverse events rate are any case of Clostridium Difficile Infection (CDI) or infection by MDR or infection-related death.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality	6 months
Infection-associated adverse events rate	Time to first infection-associated adverse events rate	6 months
Clostridium difficile Infection	Rate of infections by Clostridium difficile	6 months
Infections by MDR	Rate of infections by MDR	6 months
Mortality	Mortality	28 days
Stool colonization by C.difficile	Rate stool positive for GDH by C.difficile	6 months
Stool colonization by MDR	Rate of stool colonization by MDR	6 months
Microbiome composition	Microbiome composition	28 days
Changes of the microbiome	Changes of the microbiome	28 days
Consumption of antimicrobials during hospitalization	Consumption of antimicrobials during hospitalization	28 days
Cost of hospitalization	Real cost of hospitalization i.e medicines administered and interventions performed, in Euro, between the two groups of treatment.	28 days

Collaborators and Investigators

• Sponsor: Hellenic Institute for the Study of Sepsis
• Investigators: Principal Investigator: Anastasia Antoniadou, MD, PhD, National Kapodistrian University of Athens, Medical School

Publications and helpful links

General Publications

• Kyriazopoulou E, Karageorgos A, Liaskou-Antoniou L, Koufargyris P, Safarika A, Damoraki G, Lekakis V, Saridaki M, Adamis G, Giamarellos-Bourboulis EJ. BioFire(R) FilmArray(R) Pneumonia Panel for Severe Lower Respiratory Tract Infections: Subgroup Analysis of a Randomized Clinical Trial. Infect Dis Ther. 2021 Sep;10(3):1437-1449. doi: 10.1007/s40121-021-00459-x. Epub 2021 Jun 13.
• Kyriazopoulou E, Liaskou-Antoniou L, Adamis G, Panagaki A, Melachroinopoulos N, Drakou E, Marousis K, Chrysos G, Spyrou A, Alexiou N, Symbardi S, Alexiou Z, Lagou S, Kolonia V, Gkavogianni T, Kyprianou M, Anagnostopoulos I, Poulakou G, Lada M, Makina A, Roulia E, Koupetori M, Apostolopoulos V, Petrou D, Nitsotolis T, Antoniadou A, Giamarellos-Bourboulis EJ. Procalcitonin to Reduce Long-Term Infection-associated Adverse Events in Sepsis. A Randomized Trial. Am J Respir Crit Care Med. 2021 Jan 15;203(2):202-210. doi: 10.1164/rccm.202004-1201OC.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2017
• Primary Completion (Actual): January 20, 2019
• Study Completion (Actual): July 20, 2019

Study Registration Dates

• First Submitted: October 23, 2017
• First Submitted That Met QC Criteria: November 2, 2017
• First Posted (Actual): November 6, 2017

Study Record Updates

• Last Update Posted (Actual): December 17, 2019
• Last Update Submitted That Met QC Criteria: December 16, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Procalcitonin
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis
• Other Study ID Numbers: PROGRESS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No