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

NCT03506113 | Completed Phase 4 DMC FDA Drug

• 2 other identifiers: 29-C0707UMIN000031933
• Study Type: interventional
• Target: 206
• Locations: 1 country
• Sites: 12

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.

Conditions

Ventilator Associated Pneumonia

Keywords

Gram staining; Antimicrobial therapy; Empirical therapy; Nosocomial infection; Mechanical ventilation; Intensive care; Sepsis

Outcome Measures

Primary Outcomes (1)

• Clinical cure of VAP

  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.

  up to 22 days

Secondary Outcomes (12)

• Select of anti-pseudomonal agents as initial antibiotic therapies

  on day 1

• Select of anti-MRSA agents as initial antibiotic therapies

  on day 1

• Coverage of initial antibiotic therapies

  on day 1

• 28-day mortality

  up to 28 days

• ICU-free days

  up to 28 days

Study Arms (2)

Gram stain-guided therapy group

ACTIVE COMPARATOR

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.

Drug: Gram stain-guided antibiotic choice

Guidelines-based therapy group

ACTIVE COMPARATOR

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

Drug: Guidelines-based antibiotics choice

Interventions

Gram stain-guided antibiotic choice DRUG

The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.

Gram stain-guided therapy group

Guidelines-based antibiotics choice DRUG

Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines

Guidelines-based therapy group

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• Patients having an allergy to study medications
• Pregnant patients
• Patients discharged from ICU
• Patients diagnosed as having heart failure or atelectasis
• Patients declined to provide full life support
• Patients judged as inappropriate at the discretion of the study physician.

Sponsors & Collaborators

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

Study Sites (12)

Chukyo Hospital

Nagoya, Aichi-ken, Japan

Location

Sapporo City General Hospital

Sapporo, Hokkaido, Japan

Location

Tajima Emergency and Critical Care Medical Center

Toyooka, Hyōgo, 668-8501, Japan

Location

Hitachi General Hospital

Hitachi, Ibaraki, Japan

Location

Ebina General Hospital

Ebina, Kanagawa, Japan

Location

University of the Ryukyus Hospital

Nishihara, Okinawa, Japan

Location

Kansai Medical University Hospital

Hirakata, Osaka, Japan

Location

Kansai Medical University Medical Center

Moriguchi, Osaka, Japan

Location

Nagasaki University Hospital

Nagasaki, Japan

Location

Osaka General Medical Center

Osaka, Japan

Location

Saga University Hospital

Saga, Japan

Location

Wakayama Medical University Hospital

Wakayama, Japan

Location

Related Publications (2)

• 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.

  PMID: 35394515 DERIVED

• 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.

  PMID: 30409160 DERIVED

MeSH Terms

Conditions

Pneumonia, Ventilator-Associated; Cross Infection; Sepsis

Condition Hierarchy (Ancestors)

Healthcare-Associated Pneumonia; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Systemic Inflammatory Response Syndrome; Inflammation

Study Officials

• Jumpei Yoshimura, MD

  Osaka General Medical Center

  PRINCIPAL INVESTIGATOR

• Kazuma Yamakawa, MD, PhD

  Osaka General Medical Center

  STUDY DIRECTOR

• Takeshi Morimoto, MD, PhD, MPH

  Hyogo Medical University

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Dr.

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: April 23, 2018
• Study Start: April 1, 2018
• Primary Completion: June 28, 2020
• Study Completion: June 28, 2020
• Last Updated: September 21, 2022

Record last verified: 2022-09

Locations

JP (12)