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Defining Antibiotic Treatment Duration for Ventilator - Associated Lung Infection (REGARD_VAP)

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ClinicalTrials.gov Identifier: NCT03382548
Recruitment Status : Recruiting
First Posted : December 26, 2017
Last Update Posted : September 11, 2019
Sponsor:
Collaborators:
Medical Research Council
Department for International Development, United Kingdom
Mahidol Oxford Tropical Medicine Research Unit
Information provided by (Responsible Party):
University of Oxford

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.

This study aims to show non-inferiority of short antibiotic treatment duration (7 days or less) versus long antibiotic therapy (8 days or more) for VAP. 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 noninferior 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.


Condition or disease Intervention/treatment Phase
Ventilator Associated Pneumonia Pneumonia, Bacterial Drug: Reducing Antibiotics treatment duration Drug: Standard Antibiotics treatment duration Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 460 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Double (Participant, Investigator)
Masking Description: Patients will be blinded to the study, as they will not be informed of the treatment duration and likely to be sedated and unaware of the treatment regimens. Investigators will be blinded during the assessment of the participants for clinical stability based on the above-described criteria to minimise observer bias. Once conditions for stopping antibiotics are satisfied, the investigator will be unblinded and contact the primary physicians to stop antibiotics. The physicians will remain blinded until they are informed that the participant is suitable to stop antibiotics.
Primary Purpose: Treatment
Official Title: Reducing Antibiotics Treatment Duration for Ventilator-Associated Pneumonia
Actual Study Start Date : February 26, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Short antibiotic treatment duration for VAP (7 days or less) Drug: Reducing Antibiotics treatment duration
Antibiotics should be stopped at day 3 if respiratory cultures are negative and the patients fulfill a set of stringent clinical criteria signifying cardiopulmonary stability for 48 hours. If the respiratory cultures are positive, patients who fulfill the same set of clinical criteria should have their antibiotics stopped from day 5 to 7.

Active Comparator: Long antibiotic treatment duration for VAP ( 8 days or more) Drug: Standard Antibiotics treatment duration
Participants in the control (long duration) arm will receive standard care, which is antibiotic treatment for at least 7 days with the exact duration decided by the primary physician.




Primary Outcome Measures :
  1. Death within 60(±5) days of enrolment [ Time Frame: 3 years ]
  2. Ventilator-Associated Pneumonia recurrence rate within 60(±5) days of enrolment [ Time Frame: 3 years ]

Secondary Outcome Measures :
  1. Duration of mechanical ventilation [ Time Frame: 3 years ]
  2. Duration of hospitalization [ Time Frame: 3 years ]
  3. Rate of extra pulmonary MDRO infection during hospitalization [ Time Frame: 3 years ]
  4. Number of days of antibiotics during hospitalization [ Time Frame: 3 years ]
  5. Characteristics of microbiota in terms of shifts in functional and metabolic capacity by comparing alpha and beta diversity metrics between the groups of patients [ Time Frame: 3 years ]
  6. Relative abundance of the genera in the microbiota between the groups of patients [ Time Frame: 3 years ]
  7. Route of transmission of MDR Gram-negatives in ICUs by comparing genomic sequencing data [ Time Frame: 3 years ]
  8. Quality Adjusted Life Years (QALY) loss [ Time Frame: 3 years ]
    Mathematical modeling of antibiotic utilisation and sequencing data to predict outcomes

  9. Financial costs [ Time Frame: 3 years ]
    Mathematical modeling of antibiotic utilisation and sequencing data to predict outcomes

  10. Forecast rates of emergence of MDRO in ICUs [ Time Frame: 3 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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, bloodstream infections caused by alternative site(s) of infection, 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 72 hours from screening
  5. Vulnerable population including prisoners and refugees

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): NCT03382548


Contacts
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Contact: Mo Yin, MBBS (65) 6779 5555 moyin@tropmedres.ac
Contact: Ben Cooper 0863480013 ben@tropmedres.ac

Locations
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Nepal
Patan Academy of Health Science, Patan Hospital, Kathmandu Not yet recruiting
Patan, Nepal
Contact: Gyan Kayastha         
Singapore
National University Hospital, Singapore Not yet recruiting
Singapore, Singapore
Contact: Yip Hwee Seng         
Tan Tock Seng Hospital Not yet recruiting
Singapore, Singapore
Contact: Marimuthu Kalisvar         
Thailand
Thammasat University Hospital Not yet recruiting
Bangkok, Thailand
Contact: Anucha Apisarnthanarak         
Srinagarind Hospital Not yet recruiting
Khon Kaen, Thailand
Contact: Ploenchan Chetchotisakd         
Sunpasitthiprasong Hospital Recruiting
Ubon Ratchathani, Thailand
Contact: Jumlong Kittiworavej         
Sponsors and Collaborators
University of Oxford
Medical Research Council
Department for International Development, United Kingdom
Mahidol Oxford Tropical Medicine Research Unit

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Responsible Party: University of Oxford
ClinicalTrials.gov Identifier: NCT03382548     History of Changes
Other Study ID Numbers: BAC17008
First Posted: December 26, 2017    Key Record Dates
Last Update Posted: September 11, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of Oxford:
Ventilator Associated Pneumonia
Pneumonia
Additional relevant MeSH terms:
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Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Pneumonia, Ventilator-Associated
Pneumonia, Bacterial
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cross Infection
Infection
Bacterial Infections