Clinical trial NCT03382548: Defining Antibiotic Treatment Duration for Ventilator - Associated Lung Infection
Official title: Reducing Antibiotics Treatment Duration for Ventilator-Associated Pneumonia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Ventilator Associated Pneumonia
Pneumonia, Bacterial
Keywords: Ventilator Associated Pneumonia
Pneumonia
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: Department for International Development, United Kingdom
name: Mahidol Oxford Tropical Medicine Research Unit
First posted: 2017-12-26
Enrollment: 460
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomisation will be done via stratified block randomisation by the study sites to ensure participants with similar characteristics such as gender and age are distributed equally in the intervention and control groups. Randomisation will be done with a computer programme with a seed to allow reproducibility. Randomisation will be done with a 1:1 ratio. To prevent predictability of the random sequence, generation of the randomisation sequence is performed by an independent statistician and details of the randomisation generation is unavailable to all investigators. Randomisation will be allocated using sequentially numbered opaque envelopes. Fitness criteria for randomisation must be met prior to randomisation.
Primary purpose: TREATMENT

Brief summary: Intensive care units (ICUs), with high antibiotic consumption, are epicentres of antimicrobial resistance (AMR). Ventilator associated pneumonia (VAP) is the commonest hospital-acquired infection (HAI) in ICUs and is associated with a high morbidity and mortality in these vulnerable patients despite antibiotic therapy. No well-designed clinical trials studying antibiotic duration for VAP caused by predominantly non-fermenting Gram-negative bacteria have been conducted to date. Shortening antibiotic duration has the potential to improve individual patient outcomes and indirectly benefit other patients by reducing the selection pressure for multidrug resistant (MDR) bacteria within the ICU.

The study aims to demonstrate clinical non-inferiority-superiority of a short duration of antibiotics (up to 7 days) versus prolonged antibiotic therapy (as per physician preference) in adults with VAP in Asia. Patients who have been ventilated for more than 48 hours will be screened daily for signs and symptoms of VAP according to the US Centers for Disease Control and Prevention VAP criteria. Recruited patients will be reviewed daily for clinical signs of stability including temperature \<38°C for 48 hours, systolic blood pressure \>90mmHg without inotropes. Recruited patients will be randomised once they fulfill these clinical criteria of stability. In the intervention arm, antibiotics should be stopped within 7 days once the above criteria are fulfilled. In the control arm, antibiotics should be at least 7 days with the exact duration decided by the managing physicians.

The primary outcome of the study is a combined endpoint of mortality and VAP recurrence at day 60 of recruitment. The study hypothesis is that a shorter duration of treatment for VAP (7 days or less depending on clinical response) is not only noninferior, but may also be superior to a longer duration (8 days or more). The secondary outcomes of the study include clinical parameters such as rate of acquisition of MDRO hospital-acquired infections, duration of ventilation and hospitalization and days of antibiotics use. The study team will also characterise the microbiome changes in study participants according to the type and duration of antibiotics. MDROs collected will undergo whole genome sequencing for transmission dynamics study. The study is a multinational multicenter study involving hospitals in Asia.

Funder: The project will beis partly joinly funded by Medical Research Council/ Department for International Development (MRC/DfID) and Singapore National Medical Research Council (NMRC/CTG).

Grant Ref: MR/K006924/1 and MOH-000470 (MOH-CTGIIT18may-0003)

Conclusions This is a randomised controlled hierarchical non-inferiority-superiority trial being conducted in ICUs across Nepal, Thailand and Singapore. The primary outcome is a composite endpoint of death and pneumonia recurrence at day 60. Secondary outcomes include ventilator-associated events, multidrug-resistant organism infection or colonisation, total duration of antibiotic exposure, mechanical ventilation and hospitalisation. Adult patients who satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria are enrolled. Participants are assessed daily until fever subsides for \>48 hours and have stable blood pressure, then randomised to a short duration treatment strategy or a standard-of-care duration arm. Antibiotics may be stopped as early as day 3 if respiratory cultures are negative, and day 5 if respiratory cultures are positive in the short-course arm. Participants receiving standard-of-care will receive antibiotics for at least 8 days. Study participants are followed for 60 days after enrolment. An estimated 460 patients will be required to achieve 80% power to determine non-inferiority with a margin of 12%. All outcomes are compared by absolute risk differences. The conclusion of non-inferiority, and subsequently superiority, will be based on unadjusted and adjusted analyses in both the intention-to-treat and per-protocol populations.

Publication of this study

https://pubmed.ncbi.nlm.nih.gov/33986070/


Eligibility criteria: Inclusion Criteria:

1. Patients 18 years and older
2. Invasive mechanical ventilation ≥ 48 hours
3. Satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria

   * At least one of the following:

     1. temperature \> 38 °C
     2. white blood cell count ≥ 12,000 cells/mm3 or ≤ 4,000 cells/mm3
     3. altered mental status with no other causes in \>70 year-olds; AND
   * Two or more chest imaging tests demonstrating at least one of the following:

     1. new and progressive OR progressive and persistent infiltrate
     2. new and persistent OR progressive and persistent consolidation
     3. new and persistent OR progressive and persistent cavitation, AND
   * At least two of the following:

     1. new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements
     2. new onset or worsening tachypnea or dyspnea
     3. rales or bronchial breath sounds
     4. worsening gas exchange defined by oxygen desaturations (e.g., PaO2/FiO2 \<240), increased oxygen requirements or increased ventilation demand

Exclusion Criteria:

1. Poor likelihood of survival as defined by a Sepsis-related Organ Failure Assessment score (SOFA score) of \>11 points
2. Immunocompromised patients (HIV with CD4 \<200 cells/mm3, corticosteroids\> 0.5 mg/kg per day for \> 30 days, received chemotherapy in the past 3 months, solid organ or hematopoietic cell transplant)
3. Patients receiving antibiotic therapy for any other defined extra-pulmonary infections that warrant a duration of antibiotics longer than 7 days, or complications of pneumonia such as lung abscess or empyema, that warrant a duration of antibiotics longer than 7 days (excluding anti-tuberculosis treatment, antifungal medications, antibiotics meant for chronic suppression of chronic infections or chronic obstructive lung disease)
4. Patients who have been treated for VAP for more than 7 days from screening
5. Vulnerable population including prisoners and refugees

Primary outcomes:
measure: Proportion of patients who suffered either death or pneumonia recurrence within 60(±5) days of enrolment
timeFrame: 60 days
Secondary outcomes:
measure: Proportion of patients who suffered ventilator-associated events within 60(±5) days of enrolment
timeFrame: 60 days
measure: Duration of mechanical ventilation
timeFrame: 60 days
measure: Duration of hospitalization
timeFrame: 60 days
measure: Proportion of patients who acquired multidrug resistant infection or colonisation within 60(±5) days of enrolment
timeFrame: 60 days
measure: Number of days of antibiotics during hospitalization
timeFrame: From 3 months before to 60 days after enrolment
measure: Number and types of extrapulmonary infections during hospitalisation (determined from cultures taken from sterile sites)
timeFrame: 60 days
measure: Characteristics of microbiota in terms of shifts in functional and metabolic capacity by comparing alpha and beta diversity metrics between the groups of patients
timeFrame: 3 years
measure: Relative abundance of the genera in the microbiota between the groups of patients
timeFrame: 3 years
measure: Route of transmission of MDR Gram-negatives in ICUs by comparing genomic sequencing data
timeFrame: 3 years
measure: Quality Adjusted Life Years (QALY) loss
timeFrame: 3 years
measure: Financial costs
timeFrame: 3 years
Other outcomes:
Locations:
city: Kathmandu
country: Nepal
facility: Civil Hospital
city: Patan
country: Nepal
facility: Patan Academy of Health Science, Patan Hospital, Kathmandu
city: Singapore
country: Singapore
facility: National University Hospital, Singapore
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen Hospital
city: Khon Kaen
country: Thailand
facility: Srinagarind Hospital
city: Ubon Ratchathani
country: Thailand
facility: Sunpasitthiprasong Hospital
Study officials:
References:
citation: Mo Y, West TE, MacLaren G, Booraphun S, Li AY, Kayastha G, Lau YH, Chew YT, Chetchotisakd P, Tambyah PA, Limmathurotsakul D, Cooper B. Reducing antibiotic treatment duration for ventilator-associated pneumonia (REGARD-VAP): a trial protocol for a randomised clinical trial. BMJ Open. 2021 May 13;11(5):e050105. doi: 10.1136/bmjopen-2021-050105.