Beta-Lactam InfusioN Group Study

Sepsis Clinical Trial

— BLING III  

Official title:

A Phase III Randomised Controlled Trial of Continuous Beta-lactam Infusion Compared With Intermittent Beta-lactam Dosing in Critically Ill Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03213990
• Other study ID #: TGI-CCT254643
• Status: Completed
• Phase: N/A
• Start date: March 26, 2018
• Est. completion date: June 29, 2023

Study information

• Verified date: December 2023
• Source: The George Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 7203
• Est. completion date: June 29, 2023
• Est. primary completion date: April 12, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Sepsis

Intervention

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
Clinician prescribed beta-lactam antibiotic will be administered via intermittent infusion for as long as prescribed whilst in the ICU

Locations

Country	Name	City	State
Australia	The Queen Elizabeth Hospital	Adelaide	South Australia
Australia	The Wesley Hospital	Auchenflower	Queensland
Australia	Bankstown Hospital	Bankstown	New South Wales
Australia	Bendigo Hospital	Bendigo	Victoria
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Box Hill Hospital - Eastern Health	Box Hill	Victoria
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Caboolture Hospital	Caboolture	Queensland
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Royal Darwin Hospital	Casuarina	Northern Territory
Australia	St Vincents Hosptial	Darlinghurst	New South Wales
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	Geelong University Hospital	Geelong	Victoria
Australia	Gosford Hospital	Gosford	New South Wales
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Logan Hospital	Meadowbrook	Queensland
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	Redcliffe Hospital	Redcliffe	Queensland
Australia	Royal North Shore Hospital	Saint Leonards	New South Wales
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	St George Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Belgium	Universitair ziekenhuis Antwerpen	Antwerp
Belgium	ZNA Stuivenberg	Antwerpen
Belgium	Hôpital Erasme	Brussels	Anderlecht
Belgium	Universitair ziekenhuis Brussel	Brussels
Belgium	Civil Hospital Marie Curie	Charleroi
Belgium	Maria Middelares	Gent
Belgium	Universitair ziekenhuis Gent	Gent
Belgium	Clinique Saint Pierre	Ottignies
France	Centre Hospitalier Henri Duffaut	Avignon	Vaucluse
France	Brabois	Nancy
France	Nimes University Hospital	Nîmes	Nimes
France	Poitiers University Hospital	Poitiers
France	Ch Salon de Provence	Salon-de-Provence	Bouche Du Rhone
Malaysia	Hospital Universiti Sains Malaysia	Kota Bharu	Kelantan
Malaysia	University Malaya Medical Centre	Kuala Lumpur	Selangor
New Zealand	Auckland City Hospital - CVICU	Auckland
New Zealand	Auckland City Hospital - DCCM	Auckland
New Zealand	Middlmore Hospital	Auckland
New Zealand	Christchurch Hospital	Christchurch
New Zealand	Waikato Hospital	Hamilton
New Zealand	Wellington Hospital	Wellington
Sweden	Helsingborg Hospital	Helsingborg
Sweden	Skane Lund University Hospital	Lund
Sweden	Skane University Malmo Hospital	Malmo
United Kingdom	Stoke Mandeville Hospital	Aylesbury	Buckinghamshire
United Kingdom	Basingstoke and North Hampshire Hospital	Basingstoke	Hampshire
United Kingdom	Queen Elizabeth Medical Centre	Birmingham	West Midlands
United Kingdom	Blackpool Victoria Hospital	Blackpool	Lancashire
United Kingdom	Royal Bolton Hospital	Bolton	Greater Manchester
United Kingdom	Bristol Royal Infirmary	Bristol
United Kingdom	University Hospital of Wales	Cardiff	Wales
United Kingdom	Broomfield Hospital	Chelmsford	Essex
United Kingdom	The Royal Marsden	Chelsea	London
United Kingdom	Countess of Chester Hospital	Chester	Cheshire
United Kingdom	Golden Jubilee National Hospital	Clydebank	Glasgow
United Kingdom	University Hospital Coventry & Warwickshire	Coventry	Warwickshire
United Kingdom	Northumbria Specialist Emergency Hospital	Cramlington
United Kingdom	Darent Valley Hospital	Dartford	England
United Kingdom	Dorset County Hospital	Dorchester	Dorset
United Kingdom	Ninewells Hospital	Dundee
United Kingdom	Frimley Park Hospital	Frimley	Surrey
United Kingdom	Medway Maritime Hospital	Gillingham	Kent
United Kingdom	Glasgow Royal Infirmary	Glasgow
United Kingdom	Royal Surrey County Hospital	Guildford	Surrey
United Kingdom	Hereford County Hospital	Hereford	Herefordshire
United Kingdom	Hull Royal Infirmary	Hull
United Kingdom	Ipswich Hospital	Ipswich	East Suffolk
United Kingdom	Kingston Hospital	Kingston Upon Thames	Kent
United Kingdom	Guy's & St Thomas' Hospital London	Lambeth	London
United Kingdom	Charing Cross Hospital	London	Hammersmith
United Kingdom	Hammersmith Hospital	London	Shepherds Bush
United Kingdom	Kings College Hospital	London	Brixton
United Kingdom	St Marys Hospital	London	Paddington
United Kingdom	Whittington Health	London
United Kingdom	Maidstone Hospital	Maidstone	England
United Kingdom	James Cook University Hospital South Tees	Middlesbrough	South Tees
United Kingdom	Milton Keynes University Hospital	Milton Keynes	Buckinghamshire
United Kingdom	Newcastle Freeman Hospital	Newcastle	Northumberland
United Kingdom	Royal Victoria Infirmary	Newcastle	Northhumberland
United Kingdom	The Queens Medical Centre	Nottingham	Nottinghamshire
United Kingdom	Princess Royal University Hospital	Orpington	Bromley
United Kingdom	Derriford Hospital	Plymouth	England
United Kingdom	Poole Hospital	Poole	Dorset
United Kingdom	Queen Alexandra Hospital	Portsmouth	Hampshire
United Kingdom	Whiston Hospital	Rainhill	Prescot
United Kingdom	Royal Berkshire Hospital	Reading	Berkshire
United Kingdom	Queen's Hospital	Romford
United Kingdom	Salford Royal Hospital	Salford
United Kingdom	Southampton General Hospital	Southampton	Hampshire
United Kingdom	University Hospital of North Tees	Stockton-on-Tees	Durham
United Kingdom	Sunderland Royal Hospital	Sunderland	Tyne And Wear
United Kingdom	Kingsmill Hospital	Sutton In Ashfield	Nottinghamshire
United Kingdom	St Georges Hospital	Tooting	London
United Kingdom	Tunbridge Wells Hospital	Tunbridge Wells	Kent
United Kingdom	Pinderfields General Hospital	Wakefield	West Yorkshire
United Kingdom	Watford General Hospital	Watford	Hertfordshire
United Kingdom	The Royal London Hospital	Whitechapel	London
United Kingdom	Royal Hampshire County Hospital	Winchester	Hampshire

Sponsors (3)

Lead Sponsor	Collaborator
The George Institute	Australian and New Zealand Intensive Care Society Clinical Trials Group, National Health and Medical Research Council, Australia

Countries where clinical trial is conducted

Australia,  Belgium,  France,  Malaysia,  New Zealand,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	ICU length of stay	Patient assessment of time spent in the ICU	up to 90 days
Other	Hospital length of stay	Patient assessment of time spent in hospital.	up to 90 days
Other	Quality of life	Quality of life measured with the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L)	90 days after randomisation
Other	Health services use	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.	up to 90 days after randomisation
Other	Cost effectiveness analysis	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.	up to 90 days
Primary	All-cause mortality	Patient mortality status assessed at 90 days after randomisation	90 Days after randomisation
Secondary	Clinical Cure	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.	Day 14 post randomisation
Secondary	New acquisition, colonisation or infection	New acquisition, colonisation or infection with an Multi-resistant organism (MRO) or Clostridium difficile diarrhoea	up to 14 days post randomisation or hospital discharge, whichever is sooner
Secondary	All cause ICU mortality	Patient mortality status assessed at ICU discharge	up to 90 days
Secondary	All cause hospital mortality	Patient mortality status assessed at hospital discharge	up to 90 days