Clinical trial NCT03506113: GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial
Official title: GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Ventilator Associated Pneumonia
Keywords: Gram staining
Antimicrobial therapy
Empirical therapy
Nosocomial infection
Mechanical ventilation
Intensive care
Sepsis
Lead sponsor: Osaka General Medical Center
Sponsor class: OTHER
Collaborators: name: Chukyo Hospital
name: Ebina General Hospital
name: Hitachi General Hospital
name: Kansai Medical University
name: Kansai Medical University Medical Center
name: Nagasaki University
name: Saga University
name: University of the Ryukyus
name: Wakayama Medical University
name: Tajima Emergency and Critical Care Medical Center
name: Sapporo City General Hospital
First posted: 2018-04-23
Enrollment: 206
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background: Optimising the use of antibiotic agents is a pressing challenge to overcoming the rapid emergence and spread of multidrug-resistant pathogens in intensive care units (ICUs). Although Gram staining may possibly provide immediate information for predicting pathogenic bacteria, Gram stain-guided initial antibiotic treatment is not well established in the ICU setting. The investigators planned the GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial to investigate whether Gram staining can safely restrict the use of broad-spectrum antibiotics in patients with ventilator-associated pneumonia (VAP), which is one of the most common hospital-acquired infections in ICUs.

Methods/Design: The GRACE-VAP trial is a multicenter, randomised, open-label parallel-group trial to assess the non-inferiority of Gram stain-guided initial antibiotic treatment to guidelines-based initial antibiotic treatment for the primary endpoint of clinical cure rate in patients with VAP. Secondary endpoints include the coverage rates of initial antibiotic therapies, the selected rates of anti-pseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies, 28-day all-cause mortality, ICU-free days, ventilator-free days, and adverse events. Participants are randomly assigned to receive Gram stain-guided treatment or guidelines-based treatment at a ratio of 1:1. In the Gram stain group, results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. In the guidelines group, the combination of an anti-pseudomonal agent and anti-MRSA agent are administered. A total sample size of 200 was estimated to provide a power of 80% with a 1-sided alpha level of 2.5% and a non-inferiority margin of 20%, considering 10% non-evaluable participants.

Discussion: The GRACE-VAP trial is expected reveal whether Gram staining can reduce the use of broad-spectrum antibiotics without impairing patient outcomes and thereby provide evidence for an antibiotics selection strategy in patients with VAP.


Eligibility criteria: Inclusion Criteria:

* Patients undergoing mechanical ventilation in the ICU
* Patients undergoing mechanical ventilation for at least 48 hours
* Patients diagnosed as having VAP, which is defined by a modified clinical pulmonary infection score of 5 or more

Exclusion Criteria:

* Patients having an allergy to study medications
* Pregnant patients
* Patients discharged from ICU
* Patients diagnosed as having heart failure or atelectasis
* Patients administered antibiotics for more than 24 hours when they meet the inclusion criteria
* Patients declined to provide full life support
* Patients judged as inappropriate at the discretion of the study physician.

Primary outcomes:
measure: Clinical cure of VAP
timeFrame: up to 22 days
Secondary outcomes:
measure: Select of anti-pseudomonal agents as initial antibiotic therapies
timeFrame: on day 1
measure: Select of anti-MRSA agents as initial antibiotic therapies
timeFrame: on day 1
measure: Coverage of initial antibiotic therapies
timeFrame: on day 1
measure: 28-day mortality
timeFrame: up to 28 days
measure: ICU-free days
timeFrame: up to 28 days
measure: Ventilator-free days
timeFrame: up to 28 days
measure: Duration of antibiotic therapies
timeFrame: up to 28 days
measure: Need of escalation or de-escalation of antibiotic therapies
timeFrame: up to 28 days
measure: Adverse events related to antibiotics
timeFrame: up to 7 days after the end of therapy
measure: Inflammation marker
timeFrame: up to 14 days
measure: Organ failure control
timeFrame: up to 14 days
measure: Renal function
timeFrame: up to 14 days
Other outcomes:
Locations:
city: Nagoya
country: Japan
facility: Chukyo Hospital
state: Aichi
city: Sapporo
country: Japan
facility: Sapporo City General Hospital
state: Hokkaido
city: Toyooka
country: Japan
facility: Tajima Emergency and Critical Care Medical Center
state: Hyogo
city: Hitachi
country: Japan
facility: Hitachi General Hospital
state: Ibaraki
city: Ebina
country: Japan
facility: Ebina General Hospital
state: Kanagawa
city: Nishihara
country: Japan
facility: University of the Ryukyus Hospital
state: Okinawa
city: Hirakata
country: Japan
facility: Kansai Medical University Hospital
state: Osaka
city: Moriguchi
country: Japan
facility: Kansai Medical University Medical Center
state: Osaka
city: Nagasaki
country: Japan
facility: Nagasaki University Hospital
city: Osaka
country: Japan
facility: Osaka General Medical Center
city: Saga
country: Japan
facility: Saga University Hospital
city: Wakayama
country: Japan
facility: Wakayama Medical University Hospital
Study officials:
affiliation: Osaka General Medical Center
name: Jumpei Yoshimura, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Osaka General Medical Center
name: Kazuma Yamakawa, MD, PhD
role: STUDY_DIRECTOR
affiliation: Hyogo Medical University
name: Takeshi Morimoto, MD, PhD, MPH
role: STUDY_DIRECTOR
References:
citation: Yoshimura J, Yamakawa K, Ohta Y, Nakamura K, Hashimoto H, Kawada M, Takahashi H, Yamagiwa T, Kodate A, Miyamoto K, Fujimi S, Morimoto T. Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial. JAMA Netw Open. 2022 Apr 1;5(4):e226136. doi: 10.1001/jamanetworkopen.2022.6136.
citation: Yoshimura J, Yamakawa K, Kinoshita T, Ohta Y, Morimoto T. GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial: rationale and study protocol for a randomised controlled trial. Trials. 2018 Nov 8;19(1):614. doi: 10.1186/s13063-018-2971-2.