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

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ClinicalTrials.gov Identifier: NCT03506113
Recruitment Status : Recruiting
First Posted : April 23, 2018
Last Update Posted : July 6, 2018
Sponsor:
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
Information provided by (Responsible Party):
Jumpei Yoshimura, MD, Osaka General Medical Center

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.


Condition or disease Intervention/treatment Phase
Ventilator Associated Pneumonia Drug: Gram stain-guided antibiotic choice Drug: Guidelines-based antibiotics choice Phase 4

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial
Actual Study Start Date : April 1, 2018
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Drug: Gram stain-guided antibiotic choice
The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.

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
Drug: Guidelines-based antibiotics choice
Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. Select of anti-pseudomonal agents as initial antibiotic therapies [ Time Frame: on day 1 ]
  2. Select of anti-MRSA agents as initial antibiotic therapies [ Time Frame: on day 1 ]
  3. 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.

  4. 28-day mortality [ Time Frame: up to 28 days ]
  5. ICU-free days [ Time Frame: up to 28 days ]
  6. Ventilator-free days [ Time Frame: up to 28 days ]
  7. Duration of antibiotic therapies [ Time Frame: up to 28 days ]
  8. 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.

  9. 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

  10. Inflammation marker [ Time Frame: up to 14 days ]
    Laboratory marker of inflammation (CRP, PCT) on 2, 4, 6, 8, and 14 days

  11. 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).

  12. Renal function [ Time Frame: up to 14 days ]
    The investigators evaluate whether participants are performed a renal replacement therapy.



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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03506113


Contacts
Contact: Jumpei Yoshimura, MD +81-6-6692-1201 jumpei.y0210@gmail.com
Contact: Kazuma Yamakawa, MD, PhD +81-6-6692-1201 k.yamakawa0911@gmail.com

Locations
Japan
Chukyo Hospital Recruiting
Nagoya, Aichi, Japan
Contact: Akinori Osuka, MD, PhD         
Hitachi General Hospital Recruiting
Hitachi, Ibaraki, Japan
Contact: Kensuke Nakamura, MD, PhD         
Ebina General Hospital Recruiting
Ebina, Kanagawa, Japan
Contact: Takeshi Yamagiwa, MD, PhD         
University of the Ryukyus Hospital Recruiting
Nishihara, Okinawa, Japan
Contact: Takayuki Taira, MD         
Kansai Medical University Hospital Recruiting
Hirakata, Osaka, Japan
Contact: Hiroki Takahashi, MD         
Kansai Medical University Medical Center Recruiting
Moriguchi, Osaka, Japan
Contact: Masahiro Kawada, MD         
Nagasaki University Hospital Recruiting
Nagasaki, Japan
Contact: Shuhei Yamano, MD         
Osaka General Medical Center Recruiting
Osaka, Japan
Contact: Jumpei Yoshimura, MD         
Saga University Hospital Recruiting
Saga, Japan
Contact: Hiroyuki Koami, MD, PhD         
Wakayama Medical University Hospital Recruiting
Wakayama, Japan
Contact: Kyohei Miyamoto, MD         
Sponsors and Collaborators
Osaka General Medical Center
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
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

Responsible Party: Jumpei Yoshimura, MD, Dr., Osaka General Medical Center
ClinicalTrials.gov Identifier: NCT03506113     History of Changes
Other Study ID Numbers: 29-C0707
UMIN000031933 ( Registry Identifier: University hospital Medical Information Network )
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: July 6, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Keywords provided by Jumpei Yoshimura, MD, Osaka General Medical Center:
Gram staining
Antimicrobial therapy
Empirical therapy
Nosocomial infection
Mechanical ventilation
Intensive care
Sepsis

Additional relevant MeSH terms:
Pneumonia, Ventilator-Associated
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cross Infection
Infection
Ventilator-Induced Lung Injury
Lung Injury
Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents