UMIN-CTR Clinical Trial

Public title

GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial

Acronym

GRACE-VAP trial

Scientific Title

GRam stain-guided Antibiotics ChoicE for Ventilator-Associated Pneumonia (GRACE-VAP) trial

Scientific Title:Acronym

GRACE-VAP trial

Region

Japan

Condition

Ventilator-Associated Pneumonia (VAP)

Classification by specialty

Emergency medicine

Intensive care medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

To evaluate whether Gram stain-guided antibiotic treatment is non-inferior to guidelines-based treatment on the basis of the clinical cure in patients with VAP.

Basic objectives2

Bio-equivalence

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Pragmatic

Developmental phase

Phase IV

Primary outcomes

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). 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.

Key secondary outcomes

Select of anti-pseudomonal agents as initial antibiotic therapies
Select of anti-MRSA agents as initial antibiotic therapies
Coverage of initial antibiotic therapies
28-day mortality
28-day ICU-free days
28-day ventilator-free days
Need of continuous renal replacement therapy
Duration of antibiotic therapy
De-escalation or escalation
Renal impairment
Thrombocytopenia
Clostridium difficile infection
The other adverse events related to antibiotics
Inflammation marker (CRP, PCT)
Organ failure control (SOFA)

Study type

Interventional

Basic design

Parallel

Randomization

Randomized

Randomization unit

Individual

Blinding

Open -but assessor(s) are blinded

Control

Active

Stratification

YES

Dynamic allocation

YES

Institution consideration

Institution is considered as adjustment factor in dynamic allocation.

Blocking

NO

Concealment

Central registration

No. of arms

2

Purpose of intervention

Treatment

Type of intervention

Other

Interventions/Control_1

In the Gram stain 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. Specific antibiotic agents are selected according to previously recorded antimicrobial resistance patterns in each ICU. The study medication can be de-escalated or escalated to a definitive treatment level according to the results of the pathogens isolated from respiratory samples. Dose adjustments in the individual patients are performed as judged appropriate by the site investigator. Study medications are continued for at least 7 days and discontinued on the basis of the site investigator's judgement.

Interventions/Control_2

In the standard group, patients are administered the combination of an anti-pseudomonal agent and anti-MRSA agent according to IDSA/ATS guidelines. Specific antibiotic agents are selected according to previously recorded antimicrobial resistance patterns in each ICU. The study medication can be de-escalated or escalated to a definitive treatment level according to the results of the pathogens isolated from respiratory samples. Dose adjustments in the individual patients are performed as judged appropriate by the site investigator. Study medications are continued for at least 7 days and discontinued on the basis of the site investigator's judgement.

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

15

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

All patients undergoing mechanical ventilation in the ICU will be enroled in this study if they meet all the inclusion and none of the exclusion criteria. Patients will be included if they (1) are aged equal or more than 15 years; (2) have undergone mechanical ventilation for at least 48 hours; (3) are diagnosed as having VAP, which is defined by a modified clinical pulmonary infection score of 5 or more; and (4) or their representatives provide written, informed consent

Key exclusion criteria

Patients will be excluded if they (1) have an allergy to study medications; (2) are pregnant; (3) have already been discharged from the ICU; (4) are diagnosed as having heart failure or atelectasis; (5) have been administered antibiotics for more than 24 hours when they meet the inclusion criteria; (6) are declined to provide full life support; or (7) are judged as inappropriate at the discretion of the study physician.

Target sample size

200

Name of lead principal investigator

1st name	Jumpei
Middle name
Last name	Yoshimura

Organization

Osaka General Medical Center

Division name

Division of Trauma and Surgical Critical Care

Zip code

558-8558

Address

3-1-56 Bandai-Higashi, Sumiyoshi, Osaka 558-8558, Japan

TEL

+81-6-6692-1201

Email

jumpei.y0210@gmail.com

Name of contact person

1st name	Jumpei
Middle name
Last name	Yoshimura

Organization

Osaka General Medical Center

Division name

Division of Trauma and Surgical Critical Care

Zip code

558-8558

Address

3-1-56 Bandai-Higashi, Sumiyoshi, Osaka 558-8558, Japan

TEL

+81-6-6692-1201

Homepage URL

Email

jumpei.y0210@gmail.com

Institute

Division of Trauma and Surgical Critical Care, Osaka General Medical Center

Institute

Department

Personal name

Organization

Division of Trauma and Surgical Critical Care, Osaka General Medical Center

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Ethics Committee, Osaka General Medical Center

Address

3-1-56 Bandai-Higashi, Sumiyoshi, Osaka 558-8558, Japan

Tel

+81-6-6692-1201

Email

kenkyusien@gh.opho.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

長崎大学病院（長崎県）
関西医科大学附属枚方病院（大阪府）
関西医科大学総合医療センター（大阪府）
佐賀大学医学部附属病院（佐賀県）
日立総合病院（茨城県）
中京病院（愛知県）
海老名総合病院（神奈川県）
和歌山県立医科大学附属病院（和歌山県）
琉球大学医学部附属病院（沖縄県）
公立豊岡病院 但馬救命救急センター（兵庫県）
市立札幌病院（北海道）

Date of disclosure of the study information

2018

Year

03

Month

28

Day

URL releasing protocol

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-018-2971-2

Publication of results

Published

URL related to results and publications

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2790906

Number of participants that the trial has enrolled

206

Results

Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group.

Results date posted

2022

Year

12

Month

27

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

Of the 208 patients with VAP who were assessed for eligibility, 2 were excluded (1 for declining participation, and 1 for a COVID-19 diagnosis). As a result, we randomized 206 patients, 103 of whom were randomized to the Gram stain-guided group and 103 to the guideline-based group. The sample had a median age of 69 (54-78) years and was composed of 141 men (68.4%) and 65 women (31.6%). The median hospital stay from ICU admission to randomization was 4 (4-6) days. Demographic data, reason for ICU admission, morbidities, and severity of illness were well balanced between the 2 groups. Staphylococcus aureus (n = 103 [50.0%]) was the most frequently isolated bacteria from endotracheal aspirate, followed by Klebsiella spp (34 [16.5%]) and Haemophilus influenza (20 [9.7%]).

Participant flow

The trial recruited patients from ICUs of 12 tertiary referral hospitals in Japan (Chukyo Hospital, Nagoya, Aichi; Ebina General Hospital, Ebina, Kanagawa; Hitachi General Hospital, Hitachi, Ibaraki; Kansai Medical University Hospital, Hirakata, Osaka; Kansai Medical University Medical Center, Moriguchi, Osaka; Nagasaki University Hospital, Nagasaki; Osaka General Medical Center, Osaka; Saga University Hospital, Saga; Sapporo City General Hospital, Sapporo, Hokkaido; Tajima Emergency and Critical Care Medical Center, Toyooka, Hyogo; University of the Ryukyus Hospital, Nakagamigun, Okinawa; andWakayama Medical University Hospital,Wakayama) (eTable 1 in Supplement 2). An independent data center and Data and Safety Monitoring Board provided trial oversight . Patients were eligible if they were 15 years or older; had undergone mechanical ventilation for at least 48 hours; and had been diagnosed with VAP, defined as a modified Clinical Pulmonary Infection Score (mCPIS) of 5 or higher (score range: 0-10, with higher scores indicating greater likelihood of VAP).22 The exclusion criteria were known allergy to study medications, pregnancy, discharge from ICU, heart failure or atelectasis diagnosis, receipt of antibiotics for more than 24 hours after meeting the inclusion criteria, withdrawal or withholding of life support, or the discretion of the site investigator.We also excluded patients who were diagnosed with COVID-19 infection as an ex-post criterion when COVID-19 became pandemic in February 2020. Data on race and ethnicity were not collected. It was presumed that only Japanese citizens would participate in the trial.

Adverse events

There were 69 adverse events in the Gram stain-guided group and 79 in the guideline-based group. The most common adverse event was diarrhea (27 of 103 [26.2%] vs 38 of 103 [36.9%]), followed by kidney impairment (17 [16.5%] vs 19 [18.4%]) and thrombocytopenia (16 [15.6%] vs 11 [10.7%]). Among patients with diarrhea, C. difficile infection was noted in 4 patients (1 [1.0%] vs 3 [2.9%]).

Outcome measures

The primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Main results already published

Date of protocol fixation

2017

Year

03

Month

19

Day

Date of IRB

2017

Year

12

Month

06

Day

Anticipated trial start date

2018

Year

04

Month

01

Day

Last follow-up date

2021

Year

03

Month

31

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

Registered date

2018

Year

03

Month

27

Day

Last modified on

2022

Year

12

Month

27

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000036420