Ventilator Associated PneumoniaPhase 4NCT03506113
GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial
A Phase 4 study testing Gram stain-guided antibiotic choice and Guidelines-based antibiotics choice in people with Ventilator Associated Pneumonia, run by Osaka General Medical Center at 12 sites in Japan.
Trial 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). Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Ventilator Associated Pneumonia
- What is being tested?
- Gram stain-guided antibiotic choice and Guidelines-based antibiotics choice
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 206 participants
- Where
- 12 sitesJapan
- Study dates
- 1 Apr 2018to 28 Jun 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
Japan12 sites
Ebina General Hospital
Ebina, Kanagawa
Kansai Medical University Hospital
Hirakata, Osaka
Hitachi General Hospital
Hitachi, Ibaraki
Kansai Medical University Medical Center
Moriguchi, Osaka
Nagasaki University Hospital
Nagasaki
Chukyo Hospital
Nagoya, Aichi-ken
University of the Ryukyus Hospital
Nishihara, Okinawa
Osaka General Medical Center
Osaka
Saga University Hospital
Saga
Sapporo City General Hospital
Sapporo, Hokkaido
Tajima Emergency and Critical Care Medical Center
Toyooka, Hyōgo, 668-8501
Wakayama Medical University Hospital
Wakayama
About this study
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
- Being tested
- Gram stain-guided antibiotic choice, Guidelines-based antibiotics choice
- Keywords
- Gram staining, Antimicrobial therapy, Empirical therapy, Nosocomial infection, Mechanical ventilation, Intensive care, Sepsis
- Medical subject headings
- Pneumonia, Ventilator-Associated, Cross Infection, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Gram stain-guided antibiotic choiceDrug
The results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics.
Guidelines-based antibiotics choiceDrug
Patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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 Receives: Drug: Guidelines-based antibiotics choice |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: up to 22 days
Secondary outcomes (12)
Select of anti-pseudomonal agents as initial antibiotic therapies
Measured: on day 1
Select of anti-MRSA agents as initial antibiotic therapies
Measured: on day 1
Coverage of initial antibiotic therapies
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.
Measured: on day 1
28-day mortality
Measured: up to 28 days
ICU-free days
Measured: up to 28 days
Ventilator-free days
Measured: up to 28 days
Duration of antibiotic therapies
Measured: up to 28 days
Need of escalation or de-escalation of antibiotic therapies
The investigators evaluate whether antibiotic agents are changed during the treatments of VAP.
Measured: up to 28 days
Adverse events related to antibiotics
renal impairment, thrombocytopenia, diarrhoea, Clostridium difficile infection, skin rash, and seizure
Measured: up to 7 days after the end of therapy
Inflammation marker
Laboratory marker of inflammation (CRP, PCT) on 2, 4, 6, 8, and 14 days
Measured: up to 14 days
Organ failure control
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).
Measured: up to 14 days
Renal function
The investigators evaluate whether participants are performed a renal replacement therapy.
Measured: up to 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Apr 2018
- Study start1 Apr 2018
- Primary completion28 Jun 2020
- Study completion28 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Ventilator Associated PneumoniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 206 participants (actual)
Sponsor and investigators
- Lead sponsor
- Osaka General Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Chukyo Hospital, Ebina General Hospital, Hitachi General Hospital, Kansai Medical University, Nagasaki University, Saga University, University of the Ryukyus, Wakayama Medical University, Tajima Emergency and Critical Care Medical Center, Sapporo City General Hospital
- Responsible party
- Principal investigator, Jumpei Yoshimura, MD, Osaka General Medical Center
- Investigators
- Jumpei Yoshimura, MD, Principal investigator, Osaka General Medical CenterKazuma Yamakawa, MD, PhD, Study director, Osaka General Medical CenterTakeshi Morimoto, MD, PhD, MPH, Study director, Hyogo Medical University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03506113
- Sponsor's protocol ID
- 29-C0707
- Other IDs
- UMIN000031933
- Status last verified
- Sep 2022
- First submitted
- 29 Mar 2018
- Last updated
- 21 Sep 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
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.
PubMed 35394515Yoshimura 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.
PubMed 30409160
Study at a glance
From the registry record, last updated by the sponsor on 21 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- GRam Stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) Trial
- ClinicalTrials.gov ID
- NCT03506113
- Acronym / sponsor ID
- 29-C0707
- Conditions
- Ventilator Associated Pneumonia
- Keywords
- Gram staining, Antimicrobial therapy, Empirical therapy, Nosocomial infection, Mechanical ventilation, Intensive care, Sepsis
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 206 participants (actual)
- Lead sponsor
- Osaka General Medical CenterUniversity, hospital or other
- Collaborators
- Chukyo Hospital, Ebina General Hospital, Hitachi General Hospital, Kansai Medical University, Nagasaki University, Saga University, University of the Ryukyus, Wakayama Medical University, Tajima Emergency and Critical Care Medical Center, Sapporo City General Hospital
- Study start
- 1 Apr 2018 (actual)
- Primary completion
- 28 Jun 2020 (actual)
- Study completion
- 28 Jun 2020 (actual)
- First posted
- 23 Apr 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Gram stain-guided therapy group | Active comparator | Drug: Gram stain-guided antibiotic choiceThe 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. |
| Guidelines-based therapy group | Active comparator | Drug: Guidelines-based antibiotics choicePatients 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 |
Who may qualify
- Ages
- 15 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Gram stain-guided antibiotic choiceThe results of Gram staining of endotracheal aspirate are used to guide the selection of antibiotics. | Drug | Gram stain-guided therapy group |
| Guidelines-based antibiotics choicePatients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines | Drug | Guidelines-based therapy group |
Primary outcome
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.
12 secondary outcomes
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
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
Adverse events related to antibiotics
Time frame: up to 7 days after the end of therapy
Inflammation marker
Time frame: up to 14 days
Organ failure control
Time frame: up to 14 days
Renal function
Time frame: up to 14 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Sep 2022.
- Derived from this study: PubMed 35394515Yoshimura 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.
- Derived from this study: PubMed 30409160Yoshimura 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.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jumpei Yoshimura, MD principal investigator
Osaka General Medical Center
Kazuma Yamakawa, MD, PhD study director
Osaka General Medical Center
Takeshi Morimoto, MD, PhD, MPH study director
Hyogo Medical University
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Gram stain-guided antibiotic choice and Guidelines-based antibiotics choice in people with Ventilator Associated Pneumonia, run by Osaka General Medical Center at 12 sites in Japan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in Japan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical cure of VAP (time frame: up to 22 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03506113, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2022.