GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial

• ClinicalTrials.gov Identifier: NCT03506113
• Recruitment Status: Completed
• First Posted: April 23, 2018
• Last Update Posted: September 21, 2022
• Sponsor: Osaka General Medical Center
• Collaborators: Chukyo Hospital; Ebina General Hospital; Hitachi General Hospital; Kansai Medical University; Kansai Medical University Medical Center; Nagasaki University; Saga University; University of the Ryukyus; Wakayama Medical University; Tajima Emergency and Critical Care Medical Center; Sapporo City General Hospital
• Information provided by (Responsible Party): Jumpei Yoshimura, MD, Osaka General Medical Center

Tracking Information

• First Submitted Date: March 29, 2018
• First Posted Date: April 23, 2018
• Last Update Posted Date: September 21, 2022
• Actual Study Start Date: April 1, 2018
• Actual Primary Completion Date: June 28, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 20, 2018)

Clinical cure of VAP [ Time Frame: up to 22 days ]

Cure is defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings at the end of therapy (EOT), and resolution of signs and symptoms of pneumonia at the follow-up/test of cure visit (FU/TOC) conducted 7 days after EOT. Failure is defined as administration of study medication for 15 days or more, progression of radiological signs of pneumonia at EOT, or relapsed pneumonia at FU/TOC.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 20, 2018)

• Select of anti-pseudomonal agents as initial antibiotic therapies [ Time Frame: on day 1 ]
• Select of anti-MRSA agents as initial antibiotic therapies [ Time Frame: on day 1 ]
• Coverage of initial antibiotic therapies [ Time Frame: on day 1 ]
  Therapies will be considered appropriate when all pathogens isolated with at least 1+ semi-quantitative growth from endotracheal aspirates are covered by the selected antibiotic agents.
• 28-day mortality [ Time Frame: up to 28 days ]
• ICU-free days [ Time Frame: up to 28 days ]
• Ventilator-free days [ Time Frame: up to 28 days ]
• Duration of antibiotic therapies [ Time Frame: up to 28 days ]
• Need of escalation or de-escalation of antibiotic therapies [ Time Frame: up to 28 days ]
  The investigators evaluate whether antibiotic agents are changed during the treatments of VAP.
• Adverse events related to antibiotics [ Time Frame: up to 7 days after the end of therapy ]
  renal impairment, thrombocytopenia, diarrhoea, Clostridium difficile infection, skin rash, and seizure
• Inflammation marker [ Time Frame: up to 14 days ]
  Laboratory marker of inflammation (CRP, PCT) on 2, 4, 6, 8, and 14 days
• Organ failure control [ Time Frame: up to 14 days ]
  The investigators evaluate Sequential Organ Failure Assessment (SOFA) score on 2, 4, 6, 8, and 14 days. The SOFA score is made of 6 variables, each representing an organ system ( respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems). Each organ system is assigned a point value from 0 (normal) to 4 (high degree of dysfunction/failure). The total SOFA score is calculated by the sum of each 6 variables (range, 0-24).
• Renal function [ Time Frame: up to 14 days ]
  The investigators evaluate whether participants are performed a renal replacement therapy.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ventilator Associated Pneumonia

Intervention

• Drug: Gram stain-guided antibiotic choice
  The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.
• Drug: Guidelines-based antibiotics choice
  Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines

Study Arms

• Active Comparator: Gram stain-guided therapy group
  The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. The results of the Gram stains are categorised as Gram-positive cocci (GPC) chains, GPC clusters, Gram-positive bacilli (GPB), Gram-negative rods (GNR), or a combination of these. A non-pseudomonal beta-lactam antibiotic is selected when the Gram stain of the endotracheal aspirate shows only GPC chains and/or GPB. An anti-MRSA agent is selected when the Gram stain results show GPC clusters without GNR. An anti-pseudomonal agent is selected when the Gram stain results show GNR without GPC clusters. The combination of an anti-pseudomonal agent and an anti-MRSA agent is selected when the Gram stain results show both GPC clusters and GNR.
  Intervention: Drug: Gram stain-guided antibiotic choice
• Active Comparator: Guidelines-based therapy group
  Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to the Infectious Disease Society of America and the American Thoracic Society (IDSA/ATS) guidelines because 47.7% of S. aureus isolates are MRSA in Japanese ICUs
  Intervention: Drug: Guidelines-based antibiotics choice

Publications *

• 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. Erratum In: JAMA Netw Open. 2022 Oct 3;5(10):e2240335.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 19, 2022): 206
• Original Estimated Enrollment (submitted: April 20, 2018): 200
• Actual Study Completion Date: June 28, 2020
• Actual Primary Completion Date: June 28, 2020 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT03506113
• Other Study ID Numbers: 29-C0707; UMIN000031933 ( Registry Identifier: University hospital Medical Information Network )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Jumpei Yoshimura, MD, Osaka General Medical Center
• Original Responsible Party: Same as current
• Current Study Sponsor: Osaka General Medical Center
• Original Study Sponsor: Same as current

Collaborators

• Chukyo Hospital
• Ebina General Hospital
• Hitachi General Hospital
• Kansai Medical University
• Kansai Medical University Medical Center
• Nagasaki University
• Saga University
• University of the Ryukyus
• Wakayama Medical University
• Tajima Emergency and Critical Care Medical Center
• Sapporo City General Hospital

Investigators

• Principal Investigator: Jumpei Yoshimura, MD; Osaka General Medical Center
• Study Director: Kazuma Yamakawa, MD, PhD; Osaka General Medical Center
• Study Director: Takeshi Morimoto, MD, PhD, MPH; Hyogo College of Medicine

• PRS Account: Osaka General Medical Center
• Verification Date: September 2022