Clinical trial NCT03213990: Beta-Lactam InfusioN Group Study
Official title: A Phase III Randomised Controlled Trial of Continuous Beta-lactam Infusion Compared With Intermittent Beta-lactam Dosing in Critically Ill Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Sepsis
Keywords: Sepsis
Beta-lactam antibiotics
Lead sponsor: The George Institute
Sponsor class: OTHER
Collaborators: name: National Health and Medical Research Council, Australia
name: Australian and New Zealand Intensive Care Society Clinical Trials Group
First posted: 2017-07-11
Enrollment: 7203
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: All-cause mortality
timeFrame: 90 Days after randomisation
Secondary outcomes:
measure: Clinical Cure
timeFrame: Day 14 post randomisation
measure: New acquisition, colonisation or infection
timeFrame: up to 14 days post randomisation or hospital discharge, whichever is sooner
measure: All cause ICU mortality
timeFrame: up to 90 days
measure: All cause hospital mortality
timeFrame: up to 90 days
Other outcomes:
measure: ICU length of stay
timeFrame: up to 90 days
measure: Hospital length of stay
timeFrame: up to 90 days
measure: Quality of life
timeFrame: 90 days after randomisation
measure: Health services use
timeFrame: up to 90 days after randomisation
measure: Cost effectiveness analysis
timeFrame: up to 90 days
Locations:
city: Bankstown
country: Australia
facility: Bankstown Hospital
state: New South Wales
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincents Hosptial
state: New South Wales
city: Gosford
country: Australia
facility: Gosford Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Saint Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St George Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Casuarina
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Auchenflower
country: Australia
facility: The Wesley Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Caboolture
country: Australia
facility: Caboolture Hospital
state: Queensland
city: Meadowbrook
country: Australia
facility: Logan Hospital
state: Queensland
city: Redcliffe
country: Australia
facility: Redcliffe Hospital
state: Queensland
city: Southport
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: The Queen Elizabeth Hospital
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Box Hill
country: Australia
facility: Box Hill Hospital - Eastern Health
state: Victoria
city: Geelong
country: Australia
facility: Geelong University Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Brussels
country: Belgium
facility: Hôpital Erasme
state: Anderlecht
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Antwerp
country: Belgium
facility: Universitair ziekenhuis Antwerpen
city: Brussels
country: Belgium
facility: Universitair ziekenhuis Brussel
city: Charleroi
country: Belgium
facility: Civil Hospital Marie Curie
city: Gent
country: Belgium
facility: Maria Middelares
city: Gent
country: Belgium
facility: Universitair ziekenhuis Gent
city: Ottignies
country: Belgium
facility: Clinique Saint Pierre
city: Salon-de-Provence
country: France
facility: Ch Salon de Provence
state: Bouche Du Rhone
city: Nîmes
country: France
facility: Nimes University Hospital
state: Nimes
city: Avignon
country: France
facility: Centre Hospitalier Henri Duffaut
state: Vaucluse
city: Nancy
country: France
facility: Brabois
city: Poitiers
country: France
facility: Poitiers University Hospital
city: Kota Bharu
country: Malaysia
facility: Hospital Universiti Sains Malaysia
state: Kelantan
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
state: Selangor
city: Auckland
country: New Zealand
facility: Auckland City Hospital - CVICU
city: Auckland
country: New Zealand
facility: Auckland City Hospital - DCCM
city: Auckland
country: New Zealand
facility: Middlmore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Helsingborg
country: Sweden
facility: Helsingborg Hospital
city: Lund
country: Sweden
facility: Skane Lund University Hospital
city: Malmo
country: Sweden
facility: Skane University Malmo Hospital
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
state: Berkshire
city: London
country: United Kingdom
facility: Kings College Hospital
state: Brixton
city: Orpington
country: United Kingdom
facility: Princess Royal University Hospital
state: Bromley
city: Aylesbury
country: United Kingdom
facility: Stoke Mandeville Hospital
state: Buckinghamshire
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital
state: Buckinghamshire
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
state: Cheshire
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: Dorset
city: Poole
country: United Kingdom
facility: Poole Hospital
state: Dorset
city: Stockton-on-Tees
country: United Kingdom
facility: University Hospital of North Tees
state: Durham
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
state: East Suffolk
city: Dartford
country: United Kingdom
facility: Darent Valley Hospital
state: England
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
state: England
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: England
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
state: Essex
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital
state: Glasgow
city: Bolton
country: United Kingdom
facility: Royal Bolton Hospital
state: Greater Manchester
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: Hammersmith
city: Basingstoke
country: United Kingdom
facility: Basingstoke and North Hampshire Hospital
state: Hampshire
city: Portsmouth
country: United Kingdom
facility: Queen Alexandra Hospital
state: Hampshire
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: Hampshire
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
state: Hampshire
city: Hereford
country: United Kingdom
facility: Hereford County Hospital
state: Herefordshire
city: Watford
country: United Kingdom
facility: Watford General Hospital
state: Hertfordshire
city: Gillingham
country: United Kingdom
facility: Medway Maritime Hospital
state: Kent
city: Kingston Upon Thames
country: United Kingdom
facility: Kingston Hospital
state: Kent
city: Tunbridge Wells
country: United Kingdom
facility: Tunbridge Wells Hospital
state: Kent
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: Lancashire
city: Chelsea
country: United Kingdom
facility: The Royal Marsden
state: London
city: Lambeth
country: United Kingdom
facility: Guy's & St Thomas' Hospital London
state: London
city: Tooting
country: United Kingdom
facility: St Georges Hospital
state: London
city: Whitechapel
country: United Kingdom
facility: The Royal London Hospital
state: London
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
state: Northhumberland
city: Newcastle
country: United Kingdom
facility: Newcastle Freeman Hospital
state: Northumberland
city: Nottingham
country: United Kingdom
facility: The Queens Medical Centre
state: Nottinghamshire
city: Sutton In Ashfield
country: United Kingdom
facility: Kingsmill Hospital
state: Nottinghamshire
city: London
country: United Kingdom
facility: St Marys Hospital
state: Paddington
city: Rainhill
country: United Kingdom
facility: Whiston Hospital
state: Prescot
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: Shepherds Bush
city: Middlesbrough
country: United Kingdom
facility: James Cook University Hospital South Tees
state: South Tees
city: Frimley
country: United Kingdom
facility: Frimley Park Hospital
state: Surrey
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
state: Surrey
city: Sunderland
country: United Kingdom
facility: Sunderland Royal Hospital
state: Tyne And Wear
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: Wales
city: Coventry
country: United Kingdom
facility: University Hospital Coventry & Warwickshire
state: Warwickshire
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Medical Centre
state: West Midlands
city: Wakefield
country: United Kingdom
facility: Pinderfields General Hospital
state: West Yorkshire
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
city: Cramlington
country: United Kingdom
facility: Northumbria Specialist Emergency Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
city: London
country: United Kingdom
facility: Whittington Health
city: Romford
country: United Kingdom
facility: Queen's Hospital
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
Study officials:
affiliation: The George Institute
name: Jeffrey Lipman
role: STUDY_CHAIR
References:
citation: Lipman J, Brett SJ, De Waele JJ, Cotta MO, Davis JS, Finfer S, Glass P, Knowles S, McGuinness S, Myburgh J, Paterson DL, Peake S, Rajbhandari D, Rhodes A, Roberts JA, Shirwadkar C, Starr T, Taylor C, Billot L, Dulhunty JM. A protocol for a phase 3 multicentre randomised controlled trial of continuous versus intermittent beta-lactam antibiotic infusion in critically ill patients with sepsis: BLING III. Crit Care Resusc. 2019 Mar;21(1):63-68.