A Phase III Randomised Controlled Trial of Continuous Beta-lactam Infusion Compared With Intermittent Beta-lactam Dosing in Critically Ill Patients
Phase: NA
Conditions: Sepsis
Sponsor: The George Institute

COVER Page 
 
 
 
 
 
 
 
The Beta-Lactam InfusioN Group  
 
BLING III Study 
A phase III randomised controlled trial of continuous beta-lactam infusion 
compared with intermittent beta-lactam dosing in critically ill patients 
 
Protocol Number: TGI-CCT254643 
Version Number: 6.0  
Date: 01April 2022 
 
ClinicalTrials.gov Register: NCT03213990 
 
 
 

 
A collaboration between The George Institute for Global Health and critical care researchers around the world. 
PRIVILEGED AND CONFIDENTIAL 
Not for distribution beyond intended function. 
 
 
 
 
 
 
The Beta-Lactam InfusioN Group  
 
BLING III Study 
 
A phase III randomised controlled trial of continuous beta-lactam infusion 
compared with intermittent beta-lactam dosing in critically ill patients 
 
Protocol Number: TGI-CCT254643 
Version Number: 6.0  
Date: 01April 2022 
 
 
 
 
 
 

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Table of contents 
1. Protocol synopsis .................................................................................................................. 4 
1. Protocol synopsis (Cont’) ....................................................................................................... 5 
2. Administrative information ................................................................................................... 6 
2.1. 
Chief investigator ..................................................................................................................... 6 
2.2. 
Study sponsor/ Central trial coordinating centre (global) ....................................................... 6 
2.2.1. 
United Kingdom coordinating centre (regional) ............................................................... 6 
2.2.2. 
European countries coordinating centre (regional) .......................................................... 7 
2.3. 
BLING III management structure ............................................................................................. 7 
2.4. 
Funding .................................................................................................................................... 8 
2.5. 
Role of funding bodies ............................................................................................................. 8 
2.6. 
Trial registration ...................................................................................................................... 8 
2.7. 
Consumer engagement/patient and public involvement ....................................................... 8 
3. Introduction .......................................................................................................................... 8 
3.1. 
Background and rationale ........................................................................................................ 8 
3.2. 
Theoretical rationale ................................................................................................................ 9 
3.3. 
Current evidence ................................................................................................................... 10 
3.4. 
Need for a phase III study ...................................................................................................... 12 
3.5. 
Clinical significance ................................................................................................................ 12 
4. Study design ....................................................................................................................... 13 
4.1. 
Aim ......................................................................................................................................... 13 
4.2. 
Hypothesis ............................................................................................................................. 13 
4.3. 
Design .................................................................................................................................... 13 
5. Study outcomes .................................................................................................................. 13 
5.1. 
Primary outcome ................................................................................................................... 13 
5.2. 
Secondary outcomes ............................................................................................................. 13 
5.3. 
Tertiary outcomes .................................................................................................................. 13 
6. Study participants ............................................................................................................... 14 
6.1. 
Study setting .......................................................................................................................... 14 
6.2. 
Inclusion criteria .................................................................................................................... 14 
6.3. 
Exclusion criteria .................................................................................................................... 14 
7. Study interventions ............................................................................................................. 14 
7.1. 
Randomisation ....................................................................................................................... 14 
7.2. 
Study treatment regimen ...................................................................................................... 15 
7.2.1. 
Continuous infusion ........................................................................................................ 15 
7.2.2. 
Intermittent infusion ....................................................................................................... 16 
7.3. 
Premature cessation of study assigned administration method ........................................... 16 
7.4. 
Concomitant care................................................................................................................... 17 
7.5. 
Blinding .................................................................................................................................. 17 
7.6. 
Safety considerations ............................................................................................................. 17 
7.6.1. 
Precautions and adverse reactions ................................................................................. 17 
8. Study assessments .............................................................................................................. 17 
8.1. 
Screening ............................................................................................................................... 17 
8.2. 
Randomisation ....................................................................................................................... 17 
8.3. 
Baseline .................................................................................................................................. 18 
8.4. 
Intensive care unit admission ................................................................................................ 18 
8.5. 
Definition of clinical cure ....................................................................................................... 18 

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8.6. 
Definition of new MRO and Clostridium difficile diarrhoea................................................... 18 
8.7. 
Follow up at Day 90 ............................................................................................................... 18 
8.8. 
Schedule of assessments ....................................................................................................... 19 
9. Safety monitoring and reporting .......................................................................................... 20 
9.1. 
Adverse events ...................................................................................................................... 20 
9.1.1. 
Serious adverse events .................................................................................................... 20 
9.1.2. 
Suspected unexpected serious adverse reactions .......................................................... 21 
9.1.3. 
Reporting SAEs and SUSARs ............................................................................................ 21 
9.2. 
Data and Safety Monitoring Committee................................................................................ 21 
9.3. 
Study termination .................................................................................................................. 21 
10. Ethics and dissemination ............................................................................................. 22 
10.1. Ethical principles .................................................................................................................... 22 
10.2. Human Research Ethics Committee ...................................................................................... 22 
10.3. Informed consent procedures ............................................................................................... 22 
10.3.1. 
Australian context ....................................................................................................... 23 
10.3.2. 
New Zealand context ................................................................................................... 24 
10.3.3. 
United Kingdom context (specifically England and Wales) ......................................... 25 
10.3.4. 
Other contexts ............................................................................................................. 25 
10.4. Confidentiality and privacy .................................................................................................... 26 
11. Data collection and management ........................................................................................ 26 
11.1. Record retention .................................................................................................................... 27 
12. Quality control and quality assurance monitoring ................................................................ 27 
12.1. Responsibilities of the investigator ....................................................................................... 27 
12.2. Responsibilities of the central coordinating centre ............................................................... 27 
12.2.1. 
Site initiation ................................................................................................................ 27 
12.2.2. 
Monitoring during the study ....................................................................................... 27 
12.2.3. 
Site close out ............................................................................................................... 28 
12.3. Source document requirements ............................................................................................ 28 
12.4. Management of protocol deviations ..................................................................................... 28 
12.5. Direct access to data and documents .................................................................................... 28 
13. Statistical methods .............................................................................................................. 29 
13.1. Power calculation and sample size ........................................................................................ 29 
13.2. Statistical analysis plan .......................................................................................................... 29 
13.3. Interim analysis ...................................................................................................................... 29 
13.4. Pre-specified subgroup analyses ........................................................................................... 29 
14. Pre-specified sub-studies ..................................................................................................... 30 
14.1. Minimum inhibitory concentration distribution for identified infective organism ............... 30 
14.2. Pharmacokinetic-pharmacodynamic sub-study .................................................................... 30 
14.3. Health economics analysis ..................................................................................................... 30 
15. Publications and reports ...................................................................................................... 30 
15.1. Public access .......................................................................................................................... 31 
16. Proposed project timeline ................................................................................................... 31 
17. References .......................................................................................................................... 32 
 

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1. Protocol synopsis 
Title 
A phase III randomised controlled trial of continuous beta-lactam infusion 
compared with intermittent beta-lactam dosing in critically ill patients 
Short title 
The Beta-Lactam InfusioN Group (BLING) III study 
Design 
Prospective, multicentre, open, phase III, randomised controlled trial (RCT) 
Primary 
outcome 
All-cause mortality within 90 days after randomisation 
Secondary 
outcomes 
1. Clinical cure at Day 14 post randomisation 
2. New acquisition, colonisation or infection with a multi-resistant organism or 
Clostridium difficile diarrhoea up to 14 days post randomisation 
3. All-cause ICU mortality 
4. All-cause hospital mortality 
Tertiary 
outcomes 
1. ICU length of stay 
2. Hospital length of stay 
3. Duration of mechanical ventilation in ICU up to 90 days after randomisation 
4. Duration of renal replacement therapy up to 90 days after randomisation 
Intervention 
The administration of beta-lactam antibiotic will be randomised to either 
continuous infusion or intermittent infusion over 30 minutes for the treatment 
course for up to 14 days after randomisation while the patient is in the ICU. The 
choice of beta-lactam antibiotic, either piperacillin-tazobactam or meropenem, 
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. 
Sample size 
7,000 patients and extended at sites participating in the PKPD study until 600 
patients are recruited into the PK-PD study or for a period of 6 months following 
recruitment of the 7,000th participant, whichever occurs first  
Inclusion 
criteria 
1. Patient has a documented site of infection or strong suspicion of infection 
2. Patient is expected to be in the ICU the day after tomorrow 
3. Patient has been commenced on piperacillin-tazobactam or meropenem to 
treat the episode of infection 
4. Giving piperacillin-tazobactam or meropenem by intermittent infusion or 
continuous infusion is considered equally appropriate for the patient 
5. One or more organ dysfunction criteria in the previous 24 hours 
i. MAP < 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 or >2.49 mg/dL 
 
 
 

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1. Protocol synopsis (Cont’) 
Exclusion 
criteria 
1. Patient age is less than 18 years 
2. Patient has received piperacillin-tazobactam or meropenem for more than 
24 hours during current infectious episode 
3. Patient is known or suspected to be pregnant 
4. Patient has a known allergy to piperacillin-tazobactam, meropenem or 
penicillin 
5. Patient is requiring renal replacement therapy at the time of randomisation, 
including renal replacement therapy for chronic renal failure 
6. The attending physician or patient or surrogate legal decision maker is not 
committed to advanced life-support, including mechanical ventilation, 
dialysis and vasopressor administration, for at least the next 48 hours 
7. Patient’s death is deemed imminent and inevitable 
8. Patient has previously been enrolled in BLING III 
 
 

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2. Administrative information 
2.1. Chief investigator 
Name: 
Professor Jeffrey Lipman 
Address: 
Professor and Head, Anaesthesiology and Critical Care 
University of Queensland 
St Lucia QLD 4072 Australia 
Email:  
j.lipman@uq.edu.au 
2.2. Study sponsor/ Central trial coordinating centre (global) 
The George Institute for Global Health 
1 King Street Newtown NSW 2042 Australia 
Email:  
blingiii@georgeinstitute.org.au 
Phone: 
+61 (0)2 8052 4300 
Name: 
Professor John Myburgh AO 
Address: 
Director, Division of Critical Care and Trauma, The George Institute for Global Health 
 
1 King Street Newtown NSW 2042 Australia 
Email: 
jmyburgh@georgeinstitute.org.au 
Name: 
Ms Dorrilyn Rajbhandari 
Address: 
BLING III Project Manager, Division of Critical Care and Trauma, The George Institute for 
Global Health 
 
1 King Street Newtown NSW 2042 Australia 
Email: 
drajbhandari@georgeinstitute.org.au 
Name: 
Dr Naomi Hammond 
Address: 
Program Lead, Critical Care Program,  
 
The George Institute for Global Health 
 
1 King Street Newtown NSW 2042 Australia 
Email: 
nhammond@georgeinstitute.org.au 
2.2.1. 
United Kingdom coordinating centre (regional) 
Imperial College London 
Room 5L01, 5th Floor Charing Cross Hospital, 
Fulham Palace Road, London, W6 8RF, United Kingdom 
Email:  
blingiii@imperial.ac.uk 
Phone: 
+44 (0)20 3311 0211 
Name: 
Professor Stephen Brett 
Address: 
Professor of Critical Care, Imperial College London 
 
General Intensive Care Unit, Hammersmith Hospital, Du Cane Road, London, W12 0HS, 
UK 
Email: 
stephen.brett@imperial.ac.uk 
 
 

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Name: 
Dr Farah Al-Beidh 
Address: 
UK BLING III Coordinator, Clinical Trials research office, Imperial College London 
Room 5L01, 5th Floor Charing Cross Hospital, 
 
Fulham Palace Road, London, W6 8RF, United Kingdom 
Email: 
farah.al-beidh04@imperial.ac.uk 
2.2.2. 
European countries coordinating centre (regional) 
Universitair Ziekenhuis Gent 
Corneel Heymanslaan 10, 9000 Gent BELGIUM 
Email:  
blingiii@uzgent.be 
Phone: 
+32 9332 0508 
Name: 
Professor Jan De Waele 
Address: 
European Principal Investigator, Universitair Ziekenhuis Gent 
 
Corneel Heymanslaan 10, 9000 Gent BELGIUM 
Email: 
Jan.DeWaele@UGent.be  
Name: 
Ms Daisy Vermeiren 
Address: 
European BLING III Coordinator, Universitair Ziekenhuis Gent 
 
Corneel Heymanslaan 10, 9000 Gent BELGIUM 
Email: 
Daisy.Vermeiren@UZGENT.be 
2.3. BLING III management structure 
Terms of Reference for the BLING III Management Committee are defined in the BLING III 
Management Committee Charter. Management committee membership: 
1. Professor Jeffrey Lipman (CHAIR), Professor and Head, Anaesthesiology and Critical Care, 
University of Queensland, QLD, Australia 
2. Professor Stephen Brett, Consultant in Intensive Care Medicine, Imperial College Healthcare NHS 
Trust and Professor of Critical Care, Department of surgery and Cancer, Imperial College London, 
United Kingdom 
3. Dr Menino Osbert (Os) Cotta, Research Fellow, Department of Intensive Care Medicine, Royal 
Brisbane and Women’s Hospital, QLD, Australia 
4. Associate Professor Joshua Davis, Infectious Diseases Physician, John Hunter Hospital, NSW, 
Australia  
5. Professor Jan De Waele, Surgical Intensivist, Department of Critical Care Medicine, Ghent 
University Hospital, Belgium 
6. Dr Joel Dulhunty, Research Fellow, Department of Intensive Care Medicine, Royal Brisbane and 
Women’s Hospital, QLD, Australia 
7. Professor Simon Finfer, Professorial Fellow, Critical Care Program, The George Institute for Global 
Health, NSW, Australia 
8. Dr Serena Knowles, Operations Lead, Critical Care Program, The George Institute for Global Health, 
NSW, Australia 
9. Dr Shay McGuinness, Director of Research and Specialist Intensivist, Cardiothoracic & Vascular 
Intensive Care Unit, Auckland City Hospital, New Zealand 
10. Professor John Myburgh, Director, Critical Care Program, The George Institute for Global Health, 
NSW, Australia  
11. Professor David Paterson, Infectious Diseases Physician, Royal Brisbane and Women’s Hospital, 
QLD, Australia 

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12. Professor Sandra Peake, Senior Staff Specialist, Department of Intensive Care Medicine, The 
Queen Elizabeth Hospital, SA, Australia 
13. Ms Dorrilyn Rajbhandari (BLING III study Project Manager), Critical Care Program, The George 
Institute for Global Health, NSW, Australia 
14. Professor Andrew Rhodes, Consultant in Anaesthesia and Intensive Care Medicine and Chair of 
the Children's, Women's, Diagnostics, Therapies and Critical Care Division of St George’s 
Healthcare NHS Trust, United Kingdom 
15. Professor Jason Roberts, Pharmacist Consultant, Royal Brisbane and Women’s Hospital, and 
Professor of Medicine and Pharmacy, The University of Queensland, QLD, Australia  
16. Professor Claire Roger, Intensive Care Physician, Surgical Intensive Care Unit, Nimes University 
Hospital, Nimes, France 
17. Dr Charudatt Shirwadkar, Intensive Care Specialist, Blacktown Hospital, NSW, Australia 
18. Ms Therese Starr (Research Coordinator), Department of Intensive Care Medicine, Royal Brisbane 
and Women’s Hospital, QLD, Australia 
19. Dr Colman Taylor, Research Fellow, Critical Care Program, The George Institute for Global Health, 
NSW, Australia 
2.4. Funding  
This study is funded by an Australian National Health and Medical Research Council (NHMRC) project 
grant (APP1121481). Funding will be sought from additional funding bodies for study costs outside of 
Australia. 
2.5. Role of funding bodies 
The study will be designed and conducted, and the results analysed, presented and published by the 
investigators independent of the funding agencies. 
2.6. Trial registration  
This protocol has been registered on the following clinical trial registry; ClinicalTrials.gov Register: 
NCT03212990 
2.7. Consumer engagement/patient and public involvement 
Consumer engagement has been and will be sought to inform study procedures and information 
materials for patients, families and the community. The Royal Brisbane and Women’s Hospital 
Consumer Advisory Group has reviewed a number of study documents prior to submission to the lead 
(Australian) Human Research Ethics Committee (HREC) and will continue to be consulted as needed 
throughout the study. 
3. Introduction 
3.1. Background and rationale 
Defined as life-threatening organ dysfunction due to infection,1 sepsis is a major cause of mortality 
worldwide.2-5 Gram-positive and Gram-negative bacteria, either alone or in combination with other 
pathogens, are the leading cause of sepsis.6 
Recent longitudinal data from Australia and New Zealand show the incidence of sepsis-related 
admissions to the Intensive Care Unit (ICU) is on the rise with 2,700 patient admissions in 2000 
increasing to over 12,500 in 2012.7 Rising rates of sepsis have also been reported internationally.8 

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Hospital costs for each episode of severe sepsis have been estimated at USD 19,330 (AUD 27,500) in 
a United States study to Euro 35,185 (AUD 53,700) in a European study,8,9 with no comparable data 
available from Australia and New Zealand. 
Hospital mortality from severe sepsis in Australia and New Zealand has shown an annual absolute rate 
reduction of 1.3%, trending downwards from 35.0% in 2000 to 18.4% in 2012.7 Data from other 
developed countries have also shown similar, although not as profound, annual reductions in sepsis 
mortality,3,10 and wide variations in absolute hospital mortality (20-50%).2,3,11 However, although 
mortality rates are observed to be decreasing, the steady increase in sepsis incidence means that the 
number of people dying of sepsis is more than ever before and continues to rise.6 Worldwide 
estimates report that the number of people dying from sepsis each year is similar to the number of 
people dying from acute myocardial infarction, and far exceeds deaths as a result of Human 
Immunodeficiency Virus, breast cancer or stroke.6 Therefore, sepsis is a major public health concern 
and there is a worldwide imperative to define interventions and strategies to reduce morbidity and 
mortality. 
Early use of effective antibiotic therapy against the initiating infection is central in the treatment of 
patients with sepsis.12 One important class of antibiotics commonly used to treat infection in patients 
with sepsis are beta-lactam antibiotics. A multicentre point prevalence study of antibiotic usage in 
patients admitted to ICUs in Australia and New Zealand showed that beta-lactam antibiotics, such as 
meropenem and piperacillin-tazobactam, were the most commonly prescribed antibiotic class for the 
treatment of proven or suspected infections.13 Meropenem and piperacillin-tazobactam were also the 
two most commonly prescribed beta-lactam antibiotics in a prospective, multinational 
pharmacokinetic point-prevalence study conducted in 68 ICUs across 10 countries.14  
3.2. Theoretical rationale 
Since the late 1930s, beta-lactam antibiotics have been administered via intermittent infusion. 
However, there is a strong biological precedent that this mode of administration may be substantially 
less effective than administration via the use of continuous infusion in some clinical conditions.15,16 
Also known as time-dependent killing, beta-lactam antibiotics display maximal bacterial killing when 
concentrations of the antibiotic remain above four times the minimum inhibitory concentration (MIC) 
of the infective bacterial pathogen for 100% of the dosing interval.17 As highlighted in a recent editorial 
in Intensive Care Medicine, “the body of evidence suggests that application of this strategy [continuous 
infusion] may be best in severe infections, in patients with normal renal function and lung infections, 
and when less susceptible pathogens are isolated or suspected” (Figure 1).18  

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Figure 1. Patients hypothesised to have the highest likelihood to benefit from continuous infusion of 
beta-lactam antibiotics (extract from Taccone et al.)18  
3.3. Current evidence 
Recent human trials have shown that administration of beta-lactam antibiotics by continuous infusion 
significantly increases the likelihood of concentrations being maintained above the MIC of pathogens 
(Figure 2). The BLING I trial showed that plasma concentrations were more likely to exceed the 
bacterial MIC in the continuous arm compared with the intermittent arm (82% vs. 29%; p = 0.01) and 
found a higher clinical cure rate in the continuous group compared with the intermittent group (70% 
vs. 43%; p = 0.037).19 A recent single centre randomised controlled trial (RCT) also reported an 
increased microbiological eradication of the pathogen in the continuous group compared to the 
intermittent group (91% vs. 78%; p = 0.02).20 Additionally, these investigators found continuous 
infusion of the beta-lactam antibiotic to be an independent predictor of microbiological success (Odds 
Ratio = 2.98; 95% confidence interval [CI] 1.05-8.44). 
 
Figure 2. Higher plasma concentrations are maintained with continuous infusion (black line) compared 
with intermittent dosing (dotted blue line)21 
Although improved microbiological eradication has been demonstrated with continuous infusion of 
beta-lactam antibiotics, there is limited evidence that these improvements translate to better patient 

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outcomes. Three previous meta-analyses of RCTs have not demonstrated that use of continuous beta-
lactam antibiotic infusions is superior to intermittent administration in terms of clinical cure and 
survival, although studies to date have been small and underpowered, even when pooled.17,22,23 A 
more recent meta-analysis that also included observational studies found a lower mortality in the 
continuous group (Risk ratio = 0.59; 95% CI 0.41-0.83).24 Current human trials, however, have primarily 
been conducted in non-critically ill patient groups, with an overall mortality rate of only 6.4%,24 which 
is lower than that observed in critically ill patients with sepsis. Additionally, all but one study included 
in a meta-analysis by our group used higher doses in the intermittent arm.17 
In view of the above limitations associated with previous RCTs, a prospective, multicentre, double-
blind, double-dummy, phase II RCT (BLING II) was conducted in 25 ICUs in Australia, New Zealand and 
Hong Kong (n = 432).25,26 While there was no significant difference in the primary endpoint of alive 
ICU-free days at Day 28, an absolute difference in hospital mortality of 4.3% in favour of the 
continuous group (p = 0.28) and a similar directional trend at ICU discharge (2.2%, p = 0.54) and Day 
90 (1.8%, p = 0.67) was observed.26 In participants who received the study drug for 3 or more days, 
thereby representing a population with a higher degree of illness, there was a 7.4% absolute 
difference in Day 90 mortality in the continuous group (p = 0.17). Furthermore, an individual patient-
data meta-analysis of multicentre RCTs conducted to date comparing continuous and intermittent 
infusion of beta-lactam antibiotics reported lower hospital morality censored at Day 30 in the 
continuous infusion group compared with the intermittent infusion group (19.6% vs. 26.3%; Relative 
Risk = 0.74; 95% CI 0.56-1.00, p = 0.045).27 The difference in hospital mortality (Figure 3) remained 
after controlling for baseline factors in multivariate analysis (Figure 4). 
 
Figure 3. Difference in hospital mortality and 95% confidence interval for continuous infusion (CI) 
versus intermittent infusion (II)27  
 
 
Figure 4. Cox-regression 30-day survival curves for combined study population27 
 
Abbreviations: 
APACHE, Acute 
Physiology and Chronic Health 
Evaluation; HR, hazard ratio; 
NFGNB, non-fermenting Gram-
negative 
bacilli; 
RRT, 
renal 
replacement therapy. 

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3.4. Need for a phase III study 
The rationale to proceed with the BLING III study is as follows: 
1. 
Sepsis is a common condition with a high mortality burden. 
2. 
Effective antibiotics and delivery methods are an essential component of therapy for patients 
with sepsis. 
3. 
There is a strong microbiological basis for continuous infusion of antibiotics with time-dependent 
kill characteristics of which the beta-lactam antibiotic class belong to. 
4. 
There is good evidence from human trials of better achievement of therapeutic concentrations 
with continuous compared with intermittent infusion. 
5. 
Human trials have been underpowered to definitively test whether there is improved survival 
associated with continuous infusion. 
6. 
The standard of care in Australia and internationally is currently intermittent infusion. 
7. 
Continuous infusions are a viable alternative to standard intermittent infusion, which can be 
administered in a safe manner with no extra drug costs. 
8. 
There is sufficient clinical equipoise and clinician uncertainty to justify the conduct of a definitive 
phase III study. 
9. 
The research team and coordination centre have the expertise and track record to conduct a 
multi-national, multicentre RCT of global significance. 
In addition, in an era of increasingly expensive therapies, administration of beta-lactam antibiotics via 
continuous infusion, compared with intermittent infusion, represents greater cost-efficiency in terms 
of workload and labour costs, while remaining cost neutral in terms of drug costs.16,28 Similarly, there 
is no scientific evidence to suggest beta-lactam antibiotic administration by continuous infusion 
results in increased antibiotic resistance or negative sequelae compared with intermittent infusion. 
To this end, the potential survival and health economic advantages with using continuous beta-lactam 
infusion will be quantified in the proposed definitive phase III study. 
3.5. Clinical significance 
Regardless of the outcome, this study will provide vital evidence to answer the clinically important 
question of whether there is a difference in patient-centred outcomes in critically ill patients with 
sepsis administered beta-lactam antibiotics by continuous infusion versus intermittent infusion. If a 
3.5% absolute reduction in hospital mortality is observed, then this intervention has the potential to 
save over 750 lives each year in Australia and New Zealand alone (based on severe sepsis incidence 
data).29 This research will provide pivotal evidence on the optimal method of delivery of commonly 
used beta-lactam antibiotics via a phase III RCT of global relevance. 
 
 

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4. Study design 
4.1. 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. 
4.2. 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 
4.3. 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 for up to 14 days after randomisation while in the ICU. 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). 
5. Study outcomes 
5.1. Primary outcome 
All-cause mortality within 90 days after randomisation. 
5.2. Secondary outcomes 
1. Clinical cure at Day 14 post randomisation 
2. New acquisition, colonisation or infection with an multi-resistant organism (MRO) or Clostridium 
difficile diarrhoea up to 14 days post randomisation 
3. All-cause ICU mortality 
4. All-cause hospital mortality 
5.3. Tertiary outcomes 
1. ICU length of stay 
2. Hospital length of stay 
3. Duration of mechanical ventilation in ICU up to 90 days after randomisation 
4. Duration of renal replacement therapy up to 90 days after randomisation 

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6. Study participants 
6.1. Study setting 
This study will be conducted in approximately 100 ICUs worldwide, with sites anticipated in Australia, 
New Zealand, United Kingdom and Europe. 
6.2. Inclusion criteria 
1. Patient has a documented site of infection or strong suspicion of infection 
2. Patient is expected to be in the ICU the day after tomorrow 
3. Patient has been commenced on piperacillin-tazobactam or meropenem to treat the episode of 
infection 
4. Giving piperacillin-tazobactam or meropenem by intermittent infusion or continuous infusion is 
considered equally appropriate for the patient 
5. One or more organ dysfunction criteria in the previous 24 hours 
i. 
MAP < 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 or >2.49 mg/dL 
6.3. Exclusion criteria 
1. 
Patient age is less than 18 years 
2. 
Patient has received piperacillin-tazobactam or meropenem for more than 24 hours during 
current infectious episode 
3. 
Patient is known or suspected to be pregnant 
4. 
Patient has a known allergy to piperacillin-tazobactam, meropenem or penicillin 
5. 
Patient is requiring renal replacement therapy at the time of randomisation, including renal 
replacement therapy for chronic renal failure 
6. 
The attending physician or patient or surrogate legal decision maker is not committed to 
advanced life-support, including mechanical ventilation, dialysis and vasopressor administration, 
for at least the next 48 hours 
7. 
Patient’s death is deemed imminent and inevitable 
8. 
Patient has previously been enrolled in BLING III 
7. Study interventions 
7.1. Randomisation 
Randomisation will be achieved using a minimisation algorithm via a password-protected, encrypted 
web-based interface. Randomisation will be stratified according to participating site. Following 
successful randomisation, each patient will be assigned a unique ‘patient study number’ and be 
assigned an administration method of either continuous infusion or intermittent infusion over 30 
minutes. The clinician prescribed beta-lactam antibiotic (piperacillin-tazobactam or meropenem) will 
be administered via the study allocated method as per the below study treatment regimen. 

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7.2. Study treatment regimen 
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. The administration of beta-lactam antibiotic 
therapy will be commenced prior to randomisation. The amount of beta-lactam antibiotic prescribed 
(dose) should reflect the patient body size and estimated drug clearance as per standard prescribing 
practices. The dose of beta-lactam antibiotic the patient receives will be the same regardless of 
administration method allocation. Commencement of the allocated administration method should be 
as early as possible in the treatment course. 
During the study period, the treating physician can modify the beta-lactam antibiotic dose in response 
to clinical changes of the patient. If following randomisation, the treating physician decides to change 
from piperacillin-tazobactam to meropenem or vice versa, the new prescription will continue to be 
administered in the allocated method (continuous or intermittent infusion over 30 minutes). 
The beta-lactam antibiotic (piperacillin-tazobactam or meropenem) will continue to be administered 
according to the allocated study administration method until either: 1) the beta-lactam antibiotic is 
ceased by the treating physician, 2) the patient is discharged from ICU (including death), or 3) 14 days 
after randomisation, whichever is sooner. If the patient is readmitted to ICU (with ongoing beta-lactam 
antibiotic treatment) or the beta-lactam antibiotic is recommenced prior to Day 14 the study assigned 
administration method needs to be followed. After Day 14, the study assigned administration method 
does not need to be followed and the patient can receive the beta-lactam antibiotic via the standard 
administration method used at site. 
If the patient is still prescribed the beta-lactam antibiotic (piperacillin-tazobactam or meropenem) 
following ICU discharge, the standard administration method at the site will be used. For patients who 
require a change in administration method, the next scheduled intermittent infusion or 
commencement of continuous infusion should occur at a time equivalent to half the intended 
intermittent dosing interval (t50%) for the beta-lactam antibiotic. 
Therapeutic drug monitoring of the beta-lactam antibiotic (piperacillin-tazobactam or meropenem) 
administered according to the study allocated method is not permitted during study participation due 
to impact on the intervention. 
7.2.1. 
Continuous infusion 
Patients randomised to receive the beta-lactam antibiotic via continuous infusion will receive the 
prescribed dose over 24 hours following an initial bolus dose by intermittent infusion over 30 minutes. 
Participants previously on an intermittent dosing regimen that have been randomised into the 
continuous infusion arm, or following an initial bolus dose, will commence the continuous infusion at 
a time equivalent to half the intended intermittent dosing interval (t50%) for the beta-lactam antibiotic, 
e.g. t50% = 4 hours if the intended intermittent dosing interval is 8 hours (Figure 5). 
If the beta-lactam antibiotic is changed from piperacillin-tazobactam to meropenem or vice versa, and 
the allocated method of administration is continuous infusion, then a bolus dose of the new beta-
lactam antibiotic will be given and the continuous infusion commenced at a time equivalent to half 
the intended intermittent dosing interval. 

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7.2.2. 
Intermittent infusion 
Patients randomised to receive the beta-lactam antibiotic via intermittent infusion over 30 minutes 
will receive the prescribed dose at the scheduled intermittent dosing intervals. Participants previously 
on a continuous infusion dosing regimen that have been randomised into the intermittent infusion 
arm will have the continuous infusion ceased and receive the next scheduled dose by intermittent 
infusion over 30 minutes. The intermittent infusion should be given at the prescribed dosing interval. 
If the patient has previously been receiving a continuous infusion, then the continuous infusion should 
be stopped and the first intermittent infusion dose given immediately.  
If the beta-lactam antibiotic is changed from piperacillin-tazobactam to meropenem or vice versa, and 
the allocated method of administration is intermittent infusion, then the new beta-lactam antibiotic 
will commence at the next dosing interval. 
 
  
Figure 5. Commencement of randomised study assigned administration method following the last 
intermittent infusion (i.e. bolus dose) for a beta-lactam antibiotic prescribed at an 8 hourly interval 
7.3. Premature cessation of study assigned administration method 
Following randomisation, every effort should be made to ensure patients continue to receive the beta-
lactam antibiotic (piperacillin-tazobactam or meropenem) via the allocated study administration 
method as described in the protocol. 
Study administration method may be stopped in the following circumstances: 
1. 
Request to stop the study assigned administration method by the patient or their substitute 
decision maker/person responsible. The patient or their substitute decision maker/person 
responsible may request the study administration method be stopped if they decide to do so, at 
any time, without needing to give a reason. 
Consent to continue data collection and to continue follow up, in particular, to determine vital 
status as 90 days, will be sought. 
2. 
Adverse or serious adverse reaction to the beta-lactam antibiotic or to the study assigned 
administration method. 
0
4
8
12
16
20
24
Time (hours)
Loading dose
Continuous
Intermittent
Continuous infusion
Intermittent 
t50% 

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Appropriate ongoing treatment will be determined by the treating physician, including whether 
the beta-lactam antibiotic and/or study assigned administration method should be immediately 
ceased. 
The patient will remain in the study and the data collection and follow-up schedule will continue 
unchanged. 
7.4. Concomitant care 
Other aspects of patient management will be unaffected by study procedures. The treating clinicians 
will be free to provide whatever care is deemed appropriate and necessary. 
7.5. Blinding 
This is an unblinded study: study assigned administration method will be known to the treating 
clinicians. Ascertainment bias will be mitigated through blinded randomisation. 
7.6. Safety considerations 
There is no added discomfort or additional invasive procedures arising from participating in the study. 
The previous BLING I and BLING II trials demonstrated that beta-lactam antibiotics can be 
administered via continuous or intermittent infusion safely in a trial setting. For patients randomised 
to receive the beta-lactam antibiotic via continuous infusion the administration of a bolus dose and 
timing for commencement of the infusion (half the intended intermittent dosing interval) is designed 
to ensure adequate plasma levels of beta-lactam antibiotic are reached. 
7.6.1. 
Precautions and adverse reactions 
Piperacillin-tazobactam and meropenem are registered products with the Therapeutic Goods 
Administration (Australia), Medsafe (New Zealand) and the European Medicines Authority (United 
Kingdom and Europe). The treating clinician must be aware of the precautions and potential adverse 
reactions for piperacillin-tazobactam and meropenem detailed in Product Information relevant to 
their geographic location. Patients will be monitored for the known side effects of intravenous therapy 
with piperacillin-tazobactam and meropenem. 
8. Study assessments 
Study participants will be followed-up to 90 days post-randomisation, or to death, whichever is 
sooner. 
8.1. Screening 
Patients will be screened and evaluated to assess eligibility for the study. A screening log will be kept 
to monitor recruitment and report the size of the patient population from which eligible patients have 
been recruited. 
8.2. Randomisation 
The patient’s demographics will be entered into a web based randomisation system. Each eligibility 
criterion will be answered with a Yes / No response and only patients meeting all criteria will proceed 
to randomisation. 

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8.3. Baseline 
Patient characteristics (age, sex, estimated/actual weight and height), admission diagnosis and clinical 
information will be collected to assess baseline balance between each treatment group. Details on the 
site or sites of presumed or known infection will be obtained. Clinical information will allow calculation 
of the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure 
Assessment (SOFA) scores that classify illness severity in ICU patients.30,31  
8.4. Intensive care unit admission 
Daily clinical information and laboratory data will be recorded whilst the patient is in ICU for up to 90 
days post randomisation to document response to treatment and to monitor safety and compliance 
with the study protocol. 
8.5. Definition of 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. For the 
purposes of evaluating clinical cure, change of antibiotic therapy (i.e. either escalation or de-
escalation) for the same indication for which the beta-lactam antibiotic was commenced is considered 
part of the antibiotic treatment course. 
Participants discharged from hospital within 14 days following randomisation will be considered to 
meet the definition of clinical cure. However, if a participant is readmitted within 14 days of 
randomisation then the participant will be assessed against the definition of clinical cure as above, 
using information available at readmission. 
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. 
8.6. Definition of new MRO and Clostridium difficile diarrhoea 
New acquisition of colonisation or infection with an MRO will be defined as newly identified 
Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE), 
Extended-spectrum beta-lactamase (ESBL) or Carbapenem-resistant Enterobacteriaceae (CRE) or 
multidrug-resistant Pseudomonas on any routine swabs (e.g. nose, perineum or wounds) or clinically 
indicated specimens (e.g. blood, urine or endotracheal aspirates) taken between Day 1 and Day 14 
(inclusive). Multidrug-resistant Pseudomonas will be defined as a Pseudomonas species resistant to 
three or more of the following antibiotics: ceftazidime, ciprofloxacin, meropenem, gentamicin or 
piperacillin-tazobactam. Clostridium difficile diarrhoea will be defined as a stool sample sent to the 
laboratory and testing as Clostridium difficile toxin positive between Day 1 and Day 14 (inclusive). 
8.7. Follow up at Day 90 
Follow-up for the primary outcome will be until death or 90 days after randomisation, whichever is 
sooner. At Day 90, vital status, length of stay in the ICU, length of stay in hospital, date and cause of 
death (if appropriate) will be recorded. 

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8.8. Schedule of assessments 
Task 
Screening Randomisation 
Baseline 
Day 1 to 90 
Day 90 
follow-up 
Assess ability to gain consent & follow-up 
X 
 
 
 
 
Assess eligibility to enter study 
X 
 
 
 
 
Demographics & eligibility checklist 
 
X 
 
 
 
Record date and time of randomisation 
 
X 
 
 
 
Administer study treatment 
 
 
X 
 
 
Patient characteristics (estimated/actual weight 
and height) 
 
 
X 
 
 
ICU admission diagnosis 
 
 
X 
 
 
Baseline APACHE II (severity of illness) score 
components 
 
 
X 
 
 
Site or sites of presumed or known infection 
 
 
X 
 
 
Baseline SOFA scores 
 
 
X 
 
 
Planned 24-hour dose and dosing interval of the 
beta-lactam antibiotic at randomisation 
 
 
X 
 
 
Microbiological confirmation of infection 
 
 
X 
 
 
Assess for concurrent antibiotic use up to Day 14 
 
 
 
X 
 
Assessment for clinical cure: Day 14 
 
 
 
X 
 
Colonisation with an MRO or C. difficile at 14 days 
after randomisation 
 
 
 
X 
 
All beta-lactam antibiotic doses 
 
 
 
X 
 
Reason for cessation of beta-lactam antibiotic 
 
 
X 
 
Consent 
X 
Duration of mechanical ventilation 
 
 
 
X 
 
Duration of RRT 
 
 
 
X 
 
Date of ICU discharge up to Day 90 
 
 
X 
 
Vital status at ICU discharge 
 
 
X 
 
Date of hospital discharge up to Day 90 
 
 
X 
 
Vital status at hospital discharge 
 
 
X 
 
Vital status at Day 90 (including date and cause of 
death if deceased) 
 
 
 
X 
Adverse reactions 
 
X 
Protocol violations  
 
X 
 
 

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9. Safety monitoring and reporting 
It is recognised that the patient population in the ICU will experience a number of aberrations in 
laboratory values, signs and symptoms due to the severity of the underlying disease and the impact 
of standard treatments in the ICU. These will not necessarily constitute adverse events unless they are 
considered to be related to study treatment or in the site Principal Investigator’s clinical judgement 
are not recognised events consistent with the patient’s underlying disease and expected clinical 
course. 
In this study, reporting of adverse events will be restricted to events that are considered to be related 
to study assigned administration method (possibly, probably or definitely). Events collected as study 
outcomes will not be reported as adverse events. 
9.1. Adverse events 
Any adverse events thought to be related to study assigned administration method will be reported 
within 7 days of discovery. The site Principal Investigator will be responsible for determining the causal 
relationship as either possible, probable or definitely related. Notification will be by completing an 
adverse event form on the web based data management system. The central and regional 
coordinating centres will automatically receive an alert email when an adverse event form is 
completed on the web based data management system. 
All adverse events will be reviewed by staff at the coordinating centres and recorded in a central safety 
database and will be reported to the independent Data and Safety Monitoring Committee (DSMC) on 
a regular basis. The central coordinating centre will be responsible for ensuring regional coordinating 
centres and relevant participating sites are informed of adverse events. 
9.1.1. 
Serious adverse events 
Serious adverse events (SAEs) are defined as any untoward medical occurrence that meets one or 
more of the following criteria: 
1. Results in death 
2. Is life-threatening 
3. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
4. Results in persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect 
The classification of an SAE is not related to the assessment of the severity of the adverse event. An 
event that is mild in severity may be classified as an SAE based on the above criteria. Given that 
critically ill patients are likely to meet any of the above listed criteria in the course of their ICU 
admission, only SAEs that are thought to be related to the study assigned administration method will 
be reported. 
SAEs should be reported within 24 hours of participating site study staff becoming aware of the 
occurrence by completing an adverse event form on the web based data management system. A 
member of the regional or central coordinating centres will be available 24 hours a day for out of 
‘business hours’ queries regarding SAE reporting. 
 
 

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9.1.2. 
Suspected unexpected serious adverse reactions 
A suspected unexpected serious adverse reaction (SUSAR) is an Serious Adverse Drug Reaction (SADR) 
which is considered unexpected. An SADR whose nature, severity, specificity, or outcome is not 
consistent with the term or description used in the product information, should be considered 
unexpected. These will also be reported within 24 hours of participating site study staff becoming 
aware of the occurrence by completing an adverse event form on the web based data management 
system. 
9.1.3. 
Reporting SAEs and SUSARs 
The minimum information to report will include: 
1. Patient initials and study number 
2. Nature of the event 
3. Commencement and cessation of the event 
4. Outcome of the event 
5. The principal or co-investigator’s opinion of the relationship between study treatment and the 
event (possibly, probably or definitely related) 
6. Whether treatment was required for the event and what treatment was administered 
The regional coordinating centre staff will be responsible for following-up all SAEs, and SUSARs to 
ensure all details are available. The central coordinating centre is responsible for alerting other 
participating sites to the reported SAE, or SUSAR and reporting to the regulatory authorities within 
required timeframes. 
The central coordinating centre is responsible for ensuring that the local or lead HREC) or Institutional 
Review Board (IRB) and/or Research Governance Officer are informed of all SAE, and SUSAR events 
that occur, in accordance with local requirements. Copies of any reporting and correspondence to and 
from the local HREC / IRB or research governance office should also be sent to the regional 
coordinating centre. 
9.2. Data and Safety Monitoring Committee 
A DSMC independent from the coordinating centre and investigators will perform an ongoing review 
of study outcomes and overall study conduct. The DSMC will review study progress, including loss to 
follow up, study withdrawal, mortality and all adverse reactions at predetermined intervals during the 
study or as deemed appropriate by the DSMC. The primary responsibility of the DSMC is to review 
interim analyses of outcome data and to recommend to the Study Management Committee whether 
the study needs to be changed or terminated based on these analyses. 
Full details of the DSMC procedures and processes are documented in the DSMC charter. 
9.3. Study termination 
The study may be terminated at any time at the request of the study Management Committee in 
consultation with the DSMC, or a regulatory authority, with proper and timely notification of all parties 
concerned. The local or lead HREC / IRB will be informed promptly and the coordinating centre or the 
investigator will supply reason(s) for the termination or suspension, as specified by the applicable 
regulatory requirements. 

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Otherwise, the study will be considered terminated when the specified number of patients have been 
enrolled (see “Section 16: Proposed project timeline” for further details) and upon completion of all 
patient treatments and evaluations. 
10. Ethics and dissemination 
10.1. Ethical principles 
The study will be conducted in accordance with ethical principles consistent with the Declaration of 
Helsinki32 and all relevant national and local guidelines on the ethical conduct of research.33-35. 
10.2. Human Research Ethics Committee 
The protocol for this project will be reviewed by the relevant HREC / IRB for each participating site. In 
jurisdictions where single ethical review of multicentre trials is in place, one Principal Investigator 
(known as the coordinating investigator) will take responsibility for applying to a lead HREC / IRB on 
behalf of investigators covered by that committee. Each site Principal Investigator will then be 
responsible for applying for local research governance approval at their site (as required). 
Documentation of the approval of the protocol and the consent documents will be provided to the 
regional coordinating centre before the study may begin at any site. The regional coordinating centre 
will assist with this process by preparing a standard application form and template consent 
documents. The content and format of the standard information statements and consent forms will 
be adapted if necessary to comply with local HREC / IRB guidelines and requirements. 
During the trial, any amendment or modification to the study protocol should be notified to the HREC 
/ IRB by the Principal Investigator and approved by the HREC / IRB before implementation, unless the 
change is necessary to eliminate an immediate hazard to the patients, in which case the HREC / IRB 
should be informed as soon as possible thereafter. 
Each site Principal Investigator will be responsible for informing the central coordinating centre of any 
event likely to affect the safety of patients or the continued conduct of the clinical trial. The HREC / 
IRB will be notified in accordance with local requirements. 
The central coordinating centre will be responsible for producing progress reports, adverse event 
reports, and any other required documentation to the HREC / IRB in accordance with their guidelines. 
Copies of all HREC / IRB and research governance office correspondence, including approved local site 
consent documents, will be held by the central or regional coordinating centre and the relevant 
participating sites. 
10.3. Informed consent procedures 
This study involves the random assignment of the administration method, either continuous infusion 
or intermittent infusion, for two beta-lactam antibiotics (piperacillin-tazobactam or meropenem) in 
the treatment of sepsis in patients requiring intensive care. Piperacillin-tazobactam and meropenem 
are both commonly used in clinical practice for a wide range of infections and are not experimental 
products. All study related assessments are part of standard care of ICU patients requiring 
antimicrobial therapy, with the exception of follow up of patient status following discharge from 
hospital. 

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The Australian NHMRC National Statement on the Ethical Conduct in Human Research,33 the New 
Zealand Code of Health and Disability Consumers’ Rights34 and New Zealand Guidelines on Ethics in 
Health Research,35 acknowledge that research involving patients who are heavily dependent on 
medical care, such as the patients in this study, is necessary to assess and improve the efficacy and 
safety of interventions used in their treatment. 
The site Principal Investigators, or their nominated delegate, at each site is responsible for obtaining 
written informed consent in accordance with relevant HREC / IRB approval and any regulatory 
requirements. The informed consent procedure will involve a verbal explanation of the study and the 
provision of a written information sheet. There will be adequate time given to consider participation 
in the study and opportunity to ask questions. A copy of the information sheet and the signed and 
dated consent form will be supplied to the person providing written consent, as well as any other 
documentation discussed through the consent process. A copy of the information sheet and signed 
and dated consent form will be placed in the patient’s medical record at site and the original will 
remain in the trial site file. 
Where possible, written informed consent from any conscious and comprehending patient prior to 
their enrolment in the study will be obtained. Obtaining written and informed consent directly from 
patients in the ICU prior to enrolment in a clinical trial is frequently not possible as the patient is often 
unconscious, sedated, intubated and too ill to understand information relating to clinical trial 
participation. Additionally, antimicrobial therapy is usually a matter of clinical urgency and a treatment 
that must be carried out without delay to avoid adverse consequences for the patient that include the 
escalation of infection, worsening of organ dysfunction and at the extreme, may contribute to an 
increased risk of death. Where regulations allow, written consent may be obtained from a person 
other than the participant, and may include a legally recognised substitute decision maker or 
consultee. 
All interaction between research staff and potential or actual participants and their relatives will take 
into consideration the stress or emotional factors associated with critical illness and ensure that the 
dependency of potential participants and their relatives on medical personnel providing treatment 
does not compromise the freedom of a decision to participate. Consenting to participation will be 
voluntary and participants or their legally recognised substitute decision maker will be free to 
withdraw from participation at any time without giving reasons. 
In addition to the above, the following will apply to the consent process in the relevant country or 
region. 
10.3.1. Australian context 
A hierarchy for obtaining consent has been developed based on the Australian NHMRC National 
Statement on the Ethical Conduct of Human Research (Chapter 4.4: People highly dependent on 
medical care who may be unable to give consent)33 and the ANZICS Clinical Trials Group Ethics 
Handbook for Researchers.36 Under the circumstances discussed above, the approach to obtaining 
consent in Australia in this study will follow this hierarchy: 
a) Consent from patient PRIOR to randomisation 
Patients who are conscious and comprehending will be approached to give informed consent to take 
part in this study before project related activities are undertaken. Intensive care physicians are highly 

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experienced at caring for critically ill patients and also evaluating the competence of their patients to 
understand their illness and consent for therapeutic interventions. 
b) Consent from ‘substitute decision maker’ PRIOR to randomisation 
If a potential participant lacks the capacity to give consent due to their medical condition, whenever 
possible, consent will be obtained from a legally recognised substitute decision maker. Obtaining 
consent from the substitute decision maker will be approved by the relevant HREC / IRB and be in 
accordance with all applicable laws. 
c) Inclusion without prior consent with option to continue or withdraw  
Where it is not possible or practicable for the patient or the substitute decision maker to provide 
consent prior to randomisation, subject to approval by the relevant HREC / IRB and all applicable laws, 
the patient will be enrolled into the study without prior consent and as soon as possible and 
appropriate, the patient or substitute decision maker will be informed of the patient’s participation in 
the study. At this stage, the patient or substitute decision maker will be given the option to consent 
to continuing in the study or to withdraw from the study. If they request withdrawal of the study 
assigned administration method, then it will be stopped. Permission to use study-related data and 
permission to collect and use outcome data will be sought. 
d) Deceased patients 
For patients enrolled in the study under the process explained in 10.3.1c above, where the patient 
dies before consent has been obtained, permission to use study related information will be sought 
from the relevant HREC / IRB. 
e) Where informed consent cannot be obtained from the patient or substitute decision 
maker 
In circumstance that a patient never regains competency following enrolment into the trial under the 
process explained in 10.3.1c above and there are no substitute decision makers available, an approach 
will be made to the relevant HREC / IRB to request that re-identifiable study data may be retained and 
used. 
10.3.2. New Zealand context 
In New Zealand, the approach used will be consistent with section 7.4 of the Health and Disability 
Code,34 which outlines the framework for providing treatment to patients who are unable to consent 
for themselves. 
The specific approach will be:  
1. 
To consider whether the study assigned administration method and study participation is in the 
best interest of each individual patient, and  
2. 
As soon as it is practical and reasonable, to seek the advice of persons interested in the patient’s 
welfare to establish that study participation is consistent with the patient’s wishes. 
All participants who recover sufficiently will be given the opportunity to provide informed written 
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10.3.3. United Kingdom context (specifically England and Wales) 
If sites from Scotland or Northern Island participate, then local regulations will be adhered to in 
relation to persons legally capable of providing consent on behalf of the patient. 
In England and Wales, there will be a hierarchy for obtaining written informed consent and/or a 
declaration from a consultee in the following order of priority: 
a) Consent from patient PRIOR to randomisation 
Patients who are conscious and comprehending will be approached to give informed consent to take 
part in this study before project related activities are undertaken. Intensive care physicians are highly 
experienced at caring for critically ill patients and also evaluating the competence of their patients to 
understand their illness and consent for therapeutic interventions. 
b) Declaration from ‘personal consultee’ or ‘nominated consultee’ PRIOR to randomisation 
If a potential participant lacks the capacity to give consent due to their medical condition, then the 
advice of a consultee on whether the adult lacking capacity would wish to be included in the research 
study will be sought. The consultee will be provided with information about the study and asked to 
give an opinion as to whether the patient would object to taking part in the study and to sign a 
declaration. 
A ‘personal consultee’ is a person who cares for the adult lacking capacity or is interested in the 
person’s welfare (but not for remuneration or in a professional capacity).  If a personal consultee is 
not available or unwilling to give advice, then a ‘nominated consultee’ (a professional who is 
independent of the study) can do so. 
c) Inclusion without prior consent or declaration with option to continue or withdraw 
Where it is not possible or practicable for the patient to provide consent or a consultee to provide a 
declaration prior to randomisation, subject to approval by the relevant HREC / IRB and all applicable 
laws, the patient will be enrolled into the study without prior consent or declaration and as soon as 
possible and appropriate, the patient or consultee will be informed of the patient’s participation in 
the study. 
A consultee will be consulted as soon as possible to seek advice on the participant's likely views and 
feelings. As soon as possible and appropriate to approach the patient, they will be given the option to 
consent to continuing in the study or to withdraw from the study. If they request withdrawal of the 
study assigned administration method, then it will be stopped. Permission to use study-related data 
and permission to collect and use outcome data will be sought. 
For patients enrolled in the study without prior written consent, who either die or never regain 
capacity, assent from the personal or nominated consultee will constitute permission to use study 
related information. 
10.3.4. Other contexts 
In sites from other regions than those specifically mentioned above, local regulations will be adhered 
to in relation to persons legally capable of providing consent on behalf of the patient. 
We will abide by the regulations of state or country jurisdiction as approved by the relevant regulatory 
authority. 

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10.4. Confidentiality and privacy 
All patient data pertaining to the study will be stored in a computer database maintaining 
confidentiality in accordance with local legislation regarding privacy and use of health data. When 
archiving or processing data pertaining to the investigator and/or to study participants, the 
coordinating centre will take all appropriate measures to safeguard and prevent access to this data by 
any unauthorised third party. 
The site Principal Investigator will maintain the confidentiality of all study documentation and take 
measures to prevent accidental or premature destruction of these documents. The site Principal 
Investigator will retain the study documents for the minimum period required by local regulations 
after the completion or discontinuation of the study: at least 15 years in Australia and New Zealand, 
and 20 years in Belgium. The site Principal Investigator must notify the central coordinating centre 
prior to destroying any study documents following study completion or discontinuation. If the site 
Principal Investigator's situation is such that archiving can no longer be ensured by him/her, the site 
Principal Investigator will inform the central coordinating centre and the relevant records will be 
transferred to a mutually agreed designee. 
If any site Principal Investigator retires, relocates, or otherwise withdraws from conducting the study, 
the responsibility for maintaining records may be transferred to the central coordinating centre, or 
other site Principal Investigator. The central coordinating centre must be notified of and agree to the 
change. All associated documentation must also be updated. 
11. Data collection and management 
Data management will be provided by The George Institute for Global Health, Australia. The principle 
means of data collection and data processing will be electronic via a password protected website 
(electronic Case Report Form - eCRF). All computerised forms will be electronically signed by the 
authorised study staff and all changes made following the electronic signing will have an electronic 
audit trail with a signature and date. 
While in hospital, study participants will have relevant study data extracted from that routinely 
collected in the ICU clinical chart, medical record and available hospital databases. For study 
participants who have been discharged from hospital, they (or a nominated carer) will be contacted 
by a member of the research team at each site via telephone 90 days post randomisation to determine 
vital status. 
A comprehensive guide to data collection with definitions and rationale will be provided together with 
a paper version of the case report form (CRF). Paper documents will be stored in secure locked 
cabinets with access limited to authorised persons. 
A comprehensive guide to accessing the data entry forms on the website and entering all follow-up 
data will be provided in the Data Completion Manual and Operations Manual. All of these documents 
will also be available in PDF format for printing from the study website as required to assist the 
research coordinator to ensure high-quality data collection and data entry. 

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11.1. Record retention 
All paper study records, including consent documentation, paper CRFs (if used) and electronic records 
will be kept following the completion of the study:  15 years in Australia and New Zealand, and 20 
years in Belgium, and otherwise as per local regulations in other jurisdictions. 
12. Quality control and quality assurance monitoring 
12.1. Responsibilities of the investigator 
The site Principal Investigator agrees to perform the clinical trial in accordance with this clinical trial 
protocol, ICH guideline for Good Clinical Practice37 and all applicable regulatory requirements. The site 
Principal Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the central or regional coordinating centre. 
The site Principal Investigator agrees to provide reliable data and all information requested by the 
clinical trial protocol in an accurate, legible and timely manner according to the instructions provided. 
The site Principal Investigator agrees to allow representatives of the central or regional coordinating 
centre (or national coordinator for European sites) to have direct access to source documents. 
12.2. Responsibilities of the central coordinating centre 
The central coordinating centre, The George Institute for Global Health, is responsible for taking all 
reasonable steps to ensure the proper conduct of the clinical trial protocol. 
12.2.1. Site initiation 
Prior to initiation of the study at each participating site, the central or regional coordinating centre 
will be responsible for providing adequate training to the site Principal Investigator and study 
personnel. The training will cover all aspects of the study protocol and procedures and will include 
practical training on the use of the web-based randomisation system, electronic CRF website and study 
materials. The site initiation visit will be conducted by teleconference, videoconference or face-to-
face meeting at the participating site. Written and electronic materials will be supplied for study staff 
and for the education of clinical ICU staff at each participating site. 
12.2.2. Monitoring during the study 
A study monitor from the central or regional coordinating centre (or the national coordinator for 
European sites) will visit each participating study site on several occasions during the recruitment 
phase, in accordance with the Monitoring Plan. This will ensure that the study is conducted according 
to the protocol, Good Clinical Practice guidelines and relevant regional regulatory requirements. The 
main duty of the study monitor is to help the investigator and the coordinating centre maintain a high 
level of ethical, scientific, technical and regulatory quality in all aspects of the trial. 
The site Principal Investigator and study personnel will assist the monitoring staff by providing all 
appropriate documentation and being available to discuss the study. These monitoring visits will 
include, but will not be limited to, review of the following aspects: 
1. Adherence to the protocol including consistency with inclusion and exclusion criteria 
2. The completeness and accuracy of the CRFs and source documentation 
3. Patient recruitment 

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4. Adverse event documentation and reporting 
5. Study assigned administration method 
6. Compliance with the study assigned administration method 
7. Compliance with regulations 
The central coordinating centre team will conduct regular remote monitoring on the web-based 
database by applying validation and consistency rules and with regular data cleaning to ensure the 
integrity of the study data. 
12.2.3. Site close out 
At completion of the trial, a final monitoring and close out visit will be conducted by the study monitor 
in accordance with the Monitoring Plan. Secure facilities for the storage of study data for 15 years in 
Australia and New Zealand, and 20 years in Belgium, or otherwise as required by local regulations, will 
also be confirmed at this visit. 
12.3. Source document requirements 
According to the International Conference on Harmonisation guidelines for Good Clinical Practice37, 
the monitoring team will check source documents to confirm the existence of the participant and the 
integrity of the study data. Source documents include the original documents related to the trial, to 
medical treatment and to the history of the subject. Adequate and accurate source documents allow 
the investigator and the site monitor to verify the reliability and authenticity of data recorded on the 
electronic CRFs and ultimately to validate that the clinical study was carried out in accordance with 
the protocol. 
12.4. Management of protocol deviations 
A protocol deviation is an unanticipated or unintentional departure from the expected conduct of an 
approved study that is not consistent with the current research protocol or consent document. A 
protocol deviation may be an omission, addition or change in any procedure described in the protocol. 
The site investigator should not implement any deviation from or changes to the protocol without 
agreement by the study management committee and documented approval from the HREC / IRB of 
the amendment, except where necessary to eliminate an immediate hazard(s) to trial participants. In 
the event of an emergency intended to eliminate an apparent immediate hazard to participants the 
investigator may implement or omit any medical procedure as deemed appropriate. 
Substantive deviations from the protocol must be documented and promptly reported to the study 
management committee and the HREC / IRB (if applicable). The report should summarise the event 
and action taken. 
12.5. Direct access to data and documents 
The study may be audited by government regulatory authorities, local HREC / IRBs or qualified 
representatives of The George Institute for Global Health as permitted by regulations. Therefore, 
access to medical records, other source documents, such as ICU charts and other study related files, 
must be made available at all study sites for monitoring and audit purposes during the course of the 
study and after its completion. 

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Participants will not be identified by name, and confidentiality of information in medical records will 
be preserved. The confidentiality of the participant will be maintained unless disclosure is required by 
regulations. 
13. Statistical methods 
13.1. Power calculation and sample size  
The sample size for this study is based on data derived from the BLING II study and a subsequent 
individual patient meta-analysis,26,27 referenced to 90-day mortality in patients with sepsis in an 
international setting.4,29 A sample size of 7,000 (3,500 in each group) is required to achieve 90% power 
to detect an absolute risk reduction of 3.5% (i.e. a 12.7% relative risk reduction) in 90-day mortality in 
the intervention group from baseline mortality of 27.5%, with a significance level (alpha) of 0.05. From 
the calculated sample size (6,558) an estimated 5% loss to follow-up (345) was added with rounding 
up to 7,000. 
13.2. Statistical analysis plan 
The effectiveness of the intervention will be evaluated by an analysis of all randomised participants 
according to their allocated treatment group, irrespective of compliance. Initial range and logic tests 
will be performed and discrepancies corrected with the original site and data source where applicable. 
The coordinating centre will undertake analysis of results, including interim reporting to the DSMC. 
The primary outcome (all-cause mortality within 90 days after randomisation) as well as the secondary 
outcomes will be analysed using either log-binomial or logistic regression. The main intervention effect 
will be estimated as the relative risk or odds ratio of death and its 95% CI with the control arm used 
as the reference. Time-to-death will be described using Kaplan-Meier plots with differences in survival 
estimated using a Cox proportional hazard model. Tertiary outcomes will be analysed both as number 
of days alive and free of outcome (e.g., days alive and free of mechanical ventilation) and as time from 
randomisation to resolution or discharge (e.g. time to cessation of mechanical ventilation). A two-
sided p-value <0.05 will be considered evidence of a significant difference in the study outcome. 
All statistical analyses will be conducted in accordance with a detailed pre-specified statistical analysis 
plan.38 
13.3. Interim analysis 
In order to address safety concerns, at least one formal interim analysis will be conducted when 3,500 
patients (50% of planned recruitment) have completed 90-day follow-up. 
The purpose of this interim analysis is to assess safety and efficacy according to a pre-specified DSMC 
Charter. 
13.4. Pre-specified subgroup analyses 
1. Patients with or without lung infection 
2. Beta-lactam administered, either piperacillin-tazobactam or meropenem 

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14. Pre-specified sub-studies 
14.1. Minimum inhibitory concentration distribution for identified infective 
organism 
In participants with an identified infective organism, outcomes will be examined across the 
distribution of minimum inhibitory concentration values. 
14.2. Pharmacokinetic-pharmacodynamic sub-study 
A pharmacokinetic-pharmacodynamic (PK-PD) evaluation in up to 600 patients will be conducted at 
sites able to support collection and storage of blood samples. The relationship of beta-lactam 
antibiotic blood concentrations with the method of administration and with study outcomes will be 
determined. Further details will be provided in the PK-PD sub-study protocol. 
14.3. Health economics 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. 
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).39 The consent document used at participating sites will detail the inclusion of a quality of 
life questionnaire at Day 90. 
Additional schedule of assessments: 
Task 
Day 90 follow-up 
Date of ICU readmission/s & discharge up to Day 90 
X 
Date of hospital readmission/s & discharge up to Day 90 
X 
Quality of Life assessment (EQ-5D-5L) 
X 
15. Publications and reports 
The study will be conducted in the name of the ‘BLING III Study Investigators’. Central project 
coordination and data management will be provided by The George Institute for Global Health, 
Sydney, Australia. 
Authorship of publications arising from the study will be consistent with current ANZICS Clinical Trials 
Group policies with full credit assigned to all collaborating Institutions, investigators and research 
coordinators. Responsibility for the content of manuscripts will rest with the writing committee, and, 

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where listed, the chair of the writing committee will be listed first with subsequent members listed 
alphabetically. 
It is expected that findings will be disseminated via publication in high-quality peer reviewed journals 
in the medical or critical care literature. Study findings will also be presented at regional, national, and 
international intensive care conferences. 
Funding bodies will be acknowledged in all publications. 
15.1. Public access 
The protocol and statistical analysis plan will be made public prior to data analysis of the principal 
study. The participant level dataset will be made available at a time approved by the Management 
Committee. 
16. Proposed project timeline 
The study was initially estimated to be conducted over a five-year period (January 2017 to December 
2021). However, due to the significant impact on study recruitment from the SARS-CoV-2 (COVID-19) 
pandemic, it is estimated that the intended sample size of 7,000 will be reached by September 2022. 
In order to ensure maximal recruitment into the PK-PD sub-study, recruitment at sites participating in 
the PK-PD sub-study will continue beyond the intended sample size until 600 patients are recruited 
into the PK-PD sub-study or for a period of 6 months following recruitment of the 7,000th participant, 
whichever occurs first. Analysis, write-up and dissemination of results will occur over a subsequent 6-
month period, allowing for 90-day data to be obtained for all participants. 
 
 

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