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Beta-Lactam InfusioN Group Study (BLING III)

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ClinicalTrials.gov Identifier: NCT03213990
Recruitment Status : Recruiting
First Posted : July 11, 2017
Last Update Posted : February 22, 2019
Sponsor:
Collaborators:
National Health and Medical Research Council, Australia
Australian and New Zealand Intensive Care Society Clinical Trials Group
Information provided by (Responsible Party):
The George Institute

Brief Summary:

The purpose of this study is to find out whether continuous infusion of beta-lactam antibiotics or intermittent infusion or beta-lactam antibiotics, offers more health advantages to patients or if there is no difference.

The investigators will be looking to see whether patients receiving beta-lactams via one administration method or the other have a better chance of recovering from their illness. They will also be looking at long term outcomes such as quality-of-life and healthcare resource use.

Sepsis is caused by toxic substances (toxins) from bacteria and other organism entering the bloodstream from a site of infection. In some people, the infection can progress to sepsis and septic shock where the functions of organs in the body are affected. Patients suffering from sepsis and septic shock are commonly managed in the intensive care unit (ICU) where they are prescribed antibiotics as standard therapy, as well as other therapies to support the functions of the body.

Beta-lactam antibiotics are a group of antibiotics commonly used to treat infection in patients with sepsis and septic shock.

Currently, beta-lactam antibiotics are most commonly given to patients be intermittent infusions, that is, given at regular intervals throughout 24 hours. New research suggests that giving beta-lactam antibiotics as a continuous infusion may mean that antibiotic concentrations in the blood remain more consistent and may be more effective at killing bacteria.

However, the benefit to the patient by giving beta-lactams via continuous infusion has not been tested in a high-quality, large clinical trial.


Condition or disease Intervention/treatment Phase
Sepsis Other: Continuous infusion Other: Intermittent infusion Not Applicable

Detailed Description:

Aim To conduct a multicentre randomised, controlled trial (RCT) to determine whether continuous infusion of a beta-lactam antibiotic (piperacillin-tazobactam or meropenem) results in decreased all cause Day 90 mortality compared with intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis.

Hypothesis The BLING III Study will test the hypothesis that patients managed in the ICU with sepsis, the administration of beta-lactam antibiotics via continuous infusion decreases Day 90 mortality compared with intermittent infusion Design This BLING III study is a prospective, multicentre, open, phase III, RCT. Participants commenced on one of two beta-lactam antibiotics (piperacillin-tazobactam or meropenem) will be randomised to receive the beta-lactam antibiotic via either continuous infusion or intermittent infusion over 30 minutes for the treatment course while in the ICU for up to 90 days after randomisation. For participants where the beta-lactam antibiotic is subsequently changed from piperacillin-tazobactam to meropenem or vice versa for ongoing treatment of the infectious episode, the new prescription will continue to be administered in the allocated method (continuous infusion or intermittent infusion over 30 minutes).

Permuted block randomisation with variable block sizes and stratified by site will be conducted via a password-protected, secure web-based interface.

The primary endpoint for this trial will be death from all causes at 90 days.

7,000 patients will be enrolled into this study from approximately 70 ICUs worldwide, with approximately 35 ICUs in Australian and New Zealand hospitals.

For eligible patients, the administration method of beta-lactam antibiotic, either piperacillin-tazobactam or meropenem, will be randomised to either continuous infusion or intermittent infusion over 30 minutes. The choice of beta-lactam antibiotic and the dose and dosing interval (i.e. the dose the patient will receive in 24 hours) will be determined by the treating physician prior to randomisation.

For all patients, data will be collected at baseline and daily whilst in the ICU. Patients will be followed up to day 14, regardless of location in the hospital, to determine test of cure and to identify new acquisition, colonisation or infection with an multi-resistant organism. Additional follow up will occur at 90 days post randomisation.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III Randomised Controlled Trial of Continuous Beta-lactam Infusion Compared With Intermittent Beta-lactam Dosing in Critically Ill Patients
Actual Study Start Date : March 26, 2018
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

Arm Intervention/treatment
Continuous Infusion
The prescribed Beta-lactam is administered by a continuous infusion.
Other: Continuous infusion
Clinician prescribed beta-lactam antibiotic will be administered via continuous infusion for as long as prescribed whilst in the ICU

Intermittent infusion
the prescribed Beta-lactam is administered by intermittent infusion over 30 minutes
Other: Intermittent infusion
Clinician prescribed beta-lactam antibiotic will be administered via intermittent infusion for as long as prescribed whilst in the ICU




Primary Outcome Measures :
  1. All-cause mortality [ Time Frame: 90 Days after randomisation ]
    Patient mortality status assessed at 90 days after randomisation


Secondary Outcome Measures :
  1. Clinical Cure [ Time Frame: Day 14 post randomisation ]

    Clinical cure will be defined as the completion of the beta-lactam antibiotic treatment course (on or prior to Day 14) without recommencement of antibiotic therapy within 48 hours of cessation.

    Participants discharged from hospital within 14 days following randomisation will be considered to meet the definition of clinical cure. Participants who decease while receiving the antibiotic treatment course or where antibiotic therapy is ceased in the setting of death being deemed imminent and inevitable, will be assessed as not meeting the criteria for clinical cure.


  2. New acquisition, colonisation or infection [ Time Frame: up to 14 days post randomisation or hospital discharge, whichever is sooner ]
    New acquisition, colonisation or infection with an Multi-resistant organism (MRO) or Clostridium difficile diarrhoea

  3. All cause ICU mortality [ Time Frame: up to 90 days ]
    Patient mortality status assessed at ICU discharge

  4. All cause hospital mortality [ Time Frame: up to 90 days ]
    Patient mortality status assessed at hospital discharge


Other Outcome Measures:
  1. ICU length of stay [ Time Frame: up to 90 days ]
    Patient assessment of time spent in the ICU

  2. Hospital length of stay [ Time Frame: up to 90 days ]
    Patient assessment of time spent in hospital.

  3. Quality of life [ Time Frame: 90 days after randomisation ]
    Quality of life measured with the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L)

  4. Health services use [ Time Frame: up to 90 days after randomisation ]
    Additional follow up at Day 90 for the purpose of economic evaluation will be conducted for Australian, New Zealand and sites from participating regions only. Follow up at Day 90 will include recording readmission to hospital and ICU within 90 days and will assess quality of life and functional capacity using the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L) questionnaire (if not deceased).38 The consent document used at participating sites will detail the inclusion of a quality of life questionnaire at Day 90.

  5. Cost effectiveness analysis [ Time Frame: up to 90 days ]
    A cost-effectiveness analysis at 90 days following randomisation will be conducted as a nested cohort in Australian, New Zealand and other potential regional sites. Cost data will be derived from health care utilisation to Day 90, estimated through standard per diem ICU and hospital costs. The analysis will be conducted from a health care payer perspective, comparing health care utilisation costs and quality-adjusted life years gained (measured by the EQ-5D-5L) between treatment arms. Where feasible, the cost-effectiveness analysis will be conducted in other country-specific regions. Depending on the outcome from the primary trial, several further analyses are planned including a longer-term cohort study and a modelled economic evaluation. The BLING III cost-effectiveness analysis will be informed by a separate Statistical Analysis Plan.



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. Documented site of infection or strong suspicion of infection
  2. At the time of the assessment of suitability for the study, the treating physician expects the patient will require treatment in the ICU that extends beyond the next calendar day
  3. The treating physician has chosen piperacillin-tazobactam or meropenem to treat the episode of infection
  4. The treating physician is uncertain if administration of the chosen antibiotic by intermittent or continuous infusion is superior
  5. One or more organ dysfunction entry criteria in the previous 24 hours

    • i. Mean arterial pressure < 60 mmHg for at least 1 hour
    • ii. Vasopressors required for > 4 hours
    • iii. Respiratory support using supplemental high flow nasal prongs, continuous positive airway pressure, bilevel positive airway pressure or invasive mechanical ventilation for at least 1 hour
    • iv. Serum creatinine concentration > 220 µmol/L

Exclusion Criteria:

  1. Age less than 18 years
  2. Receipt of piperacillin-tazobactam or meropenem for more than 24 hours during current infectious episode
  3. Patients who are known or suspected to be pregnant
  4. Patient has a known allergy to piperacillin-tazobactam or meropenem or penicillin
  5. Receiving renal replacement therapy at the time of assessment for eligibility
  6. The treating physician is not committed to provision of advanced life-support, including mechanical ventilation, dialysis and vasopressor administration, for at least the next 48 hours
  7. Death is deemed imminent and inevitable
  8. The patient has previously been enrolled in BLING III

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): NCT03213990


Contacts
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Contact: Dorrilyn Rajbhandari +61 410 530 548 drajbhandari@georgeinstitute.org.au

  Show 89 Study Locations
Sponsors and Collaborators
The George Institute
National Health and Medical Research Council, Australia
Australian and New Zealand Intensive Care Society Clinical Trials Group
Investigators
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Study Chair: Jeffrey Lipman The George Institute

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: The George Institute
ClinicalTrials.gov Identifier: NCT03213990     History of Changes
Other Study ID Numbers: TGI-CCT254643
First Posted: July 11, 2017    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Yet to be decided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by The George Institute:
Sepsis
Beta-lactam antibiotics

Additional relevant MeSH terms:
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Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Pathologic Processes
Anti-Bacterial Agents
Lactams
beta-Lactams
Anti-Infective Agents