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Trial registered on ANZCTR


Registration number
ACTRN12612000138886
Ethics application status
Approved
Date submitted
18/01/2012
Date registered
1/02/2012
Date last updated
4/09/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase IIb randomised controlled trial of continuous beta-lactam infusion compared with intermittent beta-lactam dosing in critically ill patients BLING II
Scientific title
A phase IIb randomised controlled trial of continuous beta-lactam infusion compared with intermittent beta-lactam dosing in critically ill patients BLING II
Secondary ID [1] 279736 0
NIL
Universal Trial Number (UTN)
Trial acronym
BLING II
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe Sepsis in the Intensive Care patient 285582 0
Condition category
Condition code
Infection 285854 285854 0 0
Studies of infection and infectious agents
Blood 285855 285855 0 0
Other blood disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In critically ill patients with severe sepsis, how does continuous beta-lactam infusion compared with intermittent beta-lactam bolus dosing affect ICU-free days up to Day 28?Beta-lactam antibiotics are the class of antibiotics most commonly used to treat infection in patients with severe sepsis. In a recent point prevalence study of antibiotic usage in Australia and New Zealand conducted in conjunction with the Extended Study on Prevalence of Infection in Intensive Care (EPIC II), among ICU patients being treated for infection, 4 of the 5 most commonly used antibiotics were beta-lactams. The three most commonly prescribed beta-lactams were ticarcillin-clavulanate (23% of all antibiotics), meropenem (20% of all antibiotics), and piperacillin-tazobactam (13% of all antibiotics). Routine use of continuous infusions for beta-lactam administration was extremely low; with a point prevalence estimate of 1.8% for all beta-lactam antibiotics used in Australian and New Zealand ICUs. The theoretical rationale for administration of beta-lactams via continuous infusion is well recognised. Bacterial killing is related to the duration of time that bacteria are exposed to a concentration of antibiotic that exceeds the Minimum Inhibitory Concentration (MIC). It is well established that administration of beta-lactam antibiotics by infusion produces higher blood and tissue serum levels. While continuous infusion is superior to bolus administration in animal and in vitro models of infection in the absence of an effective immune response, two meta-analyses of the human trials conducted to date have not demonstrated that continuous infusion is superior to intermittent administration in terms of clinical cure and survival. These human trials, however, have been underpowered, even when pooled, and primarily conducted in non-critically ill patients. In addition, 13 of the 14 studies included in the meta-analysis by Roberts et al. used higher doses in the intermittent arm.
The beta-lactam antibiotic chosen by the treating physician will be randomised to continuous infusion or intermittent bolus administration. The dose and dosing interval of the antibiotic will be chosen by the treating physician so as to reflect body size and estimated drug clearance. The dose of antibiotic will be the same regardless of treatment group allocation and antibiotic dosing can be modified during the study based on predicted or actual changes to renal clearance. Dosing will continue as per clinician's discretion, ICU discharge or to a maximum of 14 days.
Intervention code [1] 284034 0
Treatment: Drugs
Comparator / control treatment
This study is a multi-centre, double-blinded, randomised, controlled trial of continuous beta-lactam infusion versus intermittent beta-lactam bolus dosing for patients who are commenced on the following antibiotics, with administered dose determined by the treating clinician: ticarcillin-clavulanate, meropenem, and piperacillin-tazobactam. For patients where the study drug is subsequently switched to flucloxacillin or dicloxacillin (e.g. for Staphylococcus aureus bacteraemia) or escalated to meropenem within 14 days of randomisation, the new beta-lactam will continue as the blinded study drug via the randomised administration method.The beta-lactam antibiotic chosen by the treating physician will be randomised to continuous infusion or intermittent bolus administration.
The dose and dosing interval of the antibiotic will be chosen by the treating physician so as to reflect body size and estimated drug clearance. The dose of antibiotic will be the same regardless of treatment group allocation and antibiotic dosing can be modified during the study based on predicted or actual changes to renal clearance. Dosing will continue as per clinician's discretion, ICU discharge or to a maximum of 14 days.
Control group
Active

Outcomes
Primary outcome [1] 286295 0
The primary outcome for this study is ICU-free days up to Day 28. Data collection will be confined to the following key variables:
Baseline variables:
Patient characteristics (age, sex)
ICU admission diagnosis
Admission APACHE II (severity of illness) score components
Site or sites of presumed or known infection
Study drug
Date of randomisation
Planned 24 hour dose and dosing interval of the study drug at randomisation
Subsequent beta lactam antibiotic and prescribed 24 hour dose (if applicable)
Concurrent antimicrobial use
Microbiological confirmation of infection
Daily blood cultures until negative growth at 48 hours post collection
Daily Sequential Organ Failure Assessment (SOFA) score up to Day 15 of study drug administration or ICU discharge (whichever is sooner)
Date of cessation of study drug blinding
Reason for cessation of study drug blinding
Date of cessation of study drug
Adverse events
Clinical response on cessation of the study drug Vital status at ICU discharge
Timepoint [1] 286295 0
This primary endpoint was chosen as it is correlated with 28-day mortality.
Vital status at hospital discharge
ICU-free days up to Day 28
90-day survival (including date of death if deceased)
The primary outcome for this study is ICU-free days up to Day 28. This primary endpoint was chosen as it is correlated with 28-day mortality (censored at hospital discharge) with a receiver operating character curve of 0.94 and a Nagelkerke R2 of 0.70 in a severe sepsis cohort from Australia and New Zealand (Dulhunty, unpublished results). ICU-free days is determined from the date of randomisation (Day 1). The number of non-ICU days post ICU discharge, and excluding days of ICU readmission, will be counted for each day a patient is alive up to Day 28; a patient who is deceased prior to ICU discharge receives a score of 0. Where a patient is discharged alive from hospital before Day 28, a follow call will be made to the patient or patient?s next of kin to determine survival status up to Day 28.
Secondary outcome [1] 295557 0
Secondary outcome measures are as follows:
1.90-day survival reviewed utilising a follow up call to the patient/next of kin to identify the patient status at day 90.
Timepoint [1] 295557 0
A 90-day survival surrogate endpoint was chosen over 28-day survival as short-term mortality is insufficient to fully capture the mortality effect associated with sepsis.
Secondary outcome [2] 295678 0
2.Clinical cure at test of cure date
Timepoint [2] 295678 0
Clinical cure will be determined from the clinical response variable which will be rated by a blinded treating physician at a test of cure date. Clinical response will be defined as follows:
1. Resolution - disappearance of all signs and symptoms related to the infection
2. Improvement - a marked or moderate reduction in the severity and/or number of signs and symptoms of infection
3. Failure - insufficient lessening of the signs and symptoms of infection to qualify as improvement, including death or indeterminate (no evaluation possible, for any reason)
Secondary outcome [3] 295679 0
3. Number of days free of cardiovascular, respiratory and renal organ failure at Day 14
Timepoint [3] 295679 0
The number of days for resolution of cardiovascular, respiratory and renal organ failure is evaluated to Day 15 (scored as 14 if organ failure resolves on Day 15) and subtracted from 14 to obtain organ failure free days at Day 14. Organ failure resolution is defined as the next calendar day from when a patient last required (i) vasopressors, (ii) had a PaO2/FiO2 less than 300 or required invasive mechanical ventilation, or (iii) had a creatinine greater than 170 micro mol/l or required renal replacement therapy.
Secondary outcome [4] 295680 0
4.Time to culture negative growth at 48 hours post collection
Timepoint [4] 295680 0
Daily blood cultures:
All patients will have a blood culture performed on the day of randomisation and each subsequent calendar day until there is no growth in a blood culture 48 hours after collection.

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Confirmed or suspected infection with new organ dysfunction, based on established entry criteria for severe sepsis
2. The treating clinician has chosen ticarcillin-clavulanate, meropenem or piperacillin-tazobactam to treat the episode of infection in Criterion 1.
3. The treating clinician is uncertain if administration of the chosen antibiotic by bolus administration or by infusion is superior.
4. At the time of the assessment of suitability for the study, the treating ICU specialist expects the patient will require treatment in the ICU that extends beyond the next calendar day.

Organ Dysfunction Entry Criteria:
The patient must meet one or more the following organ dysfunction entry criteria in the previous 24 hours:
1. Cardiovascular (shock):
An arterial systolic blood pressure (SBP) of equal to 90 mmHg or a mean arterial pressure (MAP) equal to 70 mmHg for at least one hour despite adequate fluid resuscitation or adequate intravascular volume status (as previously defined), and/or need for vasopressors to achieve a SBP or MAP target (as specified by the treating physician) for greater than one hour. Vasopressors are defined as:
a) Dopamine greater than 5 micro g/kg/min
b) Noradrenaline, adrenaline, metaraminol or phenylephrine by infusion at any dose.
2. Renal:
Acute kidney injury with serum creatinine greater than 1.5 x hospital admission creatinine or less than 0.5 ml/kg/hour for 6 hours. A patient with loss of kidney function or end-stage kidney disease (defined as the need for renal replacement therapy for more than 4 weeks or the need for dialysis for longer than 3 months) would need to meet one of the other organ failure criteria.
3. Respiratory:
Respiratory failure defined as PaO2/FiO2 equal to 200.
4. Haematology:
Platelet count of less than 80 x 109/L or a greater than 50% decrease in the platelet count from the highest recorded value within the preceding 3 days.
5. Metabolic acidosis:
Defined by one of the following:
a) pH less than 7.30
b) Base deficit greater than 5.0 mmol/L
c) A venous or arterial plasma lactate level greater than 1.5 times the upper limit of normal for the reporting laboratory.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients meeting one or more of the following criteria are to be excluded:
1. Receipt of any potential study drug for more than 24 hours prior to randomisation during this admission to the ICU
2. Age less than 18 years
3. Allergy or potential allergy to the study medications
4. Pregnancy
5. No central venous catheter access with three or more lumens
6. Receiving palliative or supportive treatment only at the time of assessment for eligibility
7. Treating physician is not committed to provision of advanced life-support including any of mechanical ventilation, dialysis, and vasopressor administration for at least the next 48 hours
8. Death is deemed imminent and inevitable
9. The patient has an underlying process that is likely to result in death before 90 days of follow up.
10. Consent has not been gained for study participation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation will be performed with randomisation stratified within study sites. Allocation status will be obtained for each participant at the time of study enrolment by an unblinded pharmacist (single point of enrolment). The sites will remain blinded to the treatment allocation i.e. continuous infusion or bolus dosing.Web-access options are being explored and will be utilised if funding permits.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Central randomisation will be performed with randomisation stratified within study sites.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This study is a multi-centre, double-blinded, randomised, controlled trial of continuous beta-lactam infusion versus intermittent beta-lactam bolus dosing for patients who are commenced on the following antibiotics, with administered dose determined by the treating clinician: ticarcillin-clavulanate, meropenem, and piperacillin-tazobactam.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 4858 0
4000
Recruitment postcode(s) [2] 4859 0
2000
Recruitment postcode(s) [3] 4860 0
3000
Recruitment postcode(s) [4] 4861 0
6000
Recruitment postcode(s) [5] 4862 0
0800
Recruitment postcode(s) [6] 4863 0
2600
Recruitment postcode(s) [7] 4864 0
5000
Recruitment outside Australia
Country [1] 4055 0
New Zealand
State/province [1] 4055 0
North Island ICU's
Country [2] 4056 0
New Zealand
State/province [2] 4056 0
South Island ICU's

Funding & Sponsors
Funding source category [1] 284535 0
Government body
Name [1] 284535 0
NHMRC
Address [1] 284535 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 284535 0
Australia
Primary sponsor type
Government body
Name
NHMRC
Address
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country
Australia
Secondary sponsor category [1] 283464 0
None
Name [1] 283464 0
Address [1] 283464 0
Country [1] 283464 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 286521 0
Royal Brisbane and Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 286521 0
Human Research Ethics Office
Level 7, Block 7
Herston Road
HERSTON QLD 4029
Royal Brisbane and Women's Hospital
Metro North Health Service District
Ethics committee country [1] 286521 0
Australia
Date submitted for ethics approval [1] 286521 0
31/01/2012
Approval date [1] 286521 0
18/04/2012
Ethics approval number [1] 286521 0

Summary
Brief summary
The primary aim of this study is to compare the effects of two approaches to the administration of beta-lactam antibiotics (continuous infusion and intermittent bolus dosing) on ICU-free days up to Day 28, with dosing at clinician discretion and independent of randomisation group. The null hypothesis is that there is no difference in ICU-free days up to Day 28 between patients assigned to continuous infusion and those assigned to standard bolus dosing.
Trial website
Trial related presentations / publications
Am J Respir Crit Care Med. First published online 22 Jul 2015 as DOI: 10.1164/rccm.201505-0857OC
A Multicenter Randomized Trial of Continuous versus Intermittent ß-Lactam Infusion in Severe Sepsis
Joel M Dulhunty, Jason A Roberts, Joshua S Davis, Steven A R Webb, Rinaldo Bellomo, Charles Gomersall, Charudatt Shirwadkar, Glenn M Eastwood, John Myburgh, David L Paterson, Therese Starr, Sanjoy K Paul, and Jeffrey Lipman

The manuscript is available in the Articles in Press section of the AJRCCM website:
http://www.atsjournals.org/doi/abs/10.1164/rccm.201505-0857OC#.VbSvbXiQdbw
Public notes

Contacts
Principal investigator
Name 33637 0
Prof Jeffrey Lipman
Address 33637 0
Royal Brisbane and Women's Hospital Level 3 Dept of Intensive Care Medicine
Ned Hanlon Building Herston road HERSTON QLD 4029
Country 33637 0
Australia
Phone 33637 0
+61 7 3646 8894
Fax 33637 0
Email 33637 0
j.lipman@uq.edu.au
Contact person for public queries
Name 16884 0
Ms Therese Starr
Address 16884 0
c/o RBWH
Dept of Intensive Care Medicine
Level 3 Ned Hanlon Bldg
Herston Road
HERSTON QLD 4029
Country 16884 0
Australia
Phone 16884 0
+61 7 3646 8894
Fax 16884 0
+61 7 3646 3542
Email 16884 0
therese.starr@health.qld.gov.au
Contact person for scientific queries
Name 7812 0
Dr Dr Joel Dulhunty
Address 7812 0
c/o RBWH
Dept of Intensive Care Medicine
Level 3 Ned Hanlon Bldg
Herston Road
HERSTON QLD 4029
Country 7812 0
Australia
Phone 7812 0
+61 7 3646 8894
Fax 7812 0
+61 7 3646 3542
Email 7812 0
Joel.Dulhunty@health.qld.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary