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Trial registered on ANZCTR


Registration number
ACTRN12613001129774
Ethics application status
Approved
Date submitted
4/10/2013
Date registered
10/10/2013
Date last updated
24/03/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Study on Clinical Outcomes of Piperacillin-Tazobactam Extended Infusion in Patients Hospitalised with a Bacterial Infection or Neutropenic Fever
Scientific title
Study on the Clinical Outcomes of Piperacillin-Tazobactam Extended 4-hour Infusion as compared to Piperacillin-Tazobactam Traditional 30-minute Infusion in Patients Hospitalised for a Bacterial Infection or Neutropenic Fever - A Prospective Clinical Trial
Secondary ID [1] 283361 0
Nil
Universal Trial Number (UTN)
U1111-1148-8097
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Infection 290258 0
Condition category
Condition code
Infection 290649 290649 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention group would receive extended 4-hour intravenous infusion of Piperacillin-Tazobactam. Piperacillin-Tazobactam extended 4-hour infusion would be dosed according to renal function.
Creatinine clearance (estimated by Cockcroft Gault equation) >/= 20ml/min: 4.5gram every 8 hours
Creatinine clearance (estimated by Cockcroft Gault equation) < 20ml/min: 4.5gram every 12 hours

Participants would receive the extended 4-hour intravenous infusion of Piperacillin-Tazobactam after treatment assignment until Piperacillin-Tazobactam was decided to be discontinued by attending physician according to clinical condition and culture sensitivity results.
Intervention code [1] 288086 0
Treatment: Drugs
Comparator / control treatment
Control group would receive traditional 30-minute intravenous infusion of Piperacillin-Tazobactam. Piperacillin-Tazobactam traditional 30-minute intravenous infusion would be dosed according to renal function.
Creatinine clearance (estimated by Cockcroft Gault equation) > 40ml/min: 4.5gram every 6 to 8 hours
Creatinine clearance (estimated by Cockcroft Gault equation) 20-40ml/min: 2.25gram every 6 hours to 4.5gram every 8 hours
Creatinine clearance (estimated by Cockcroft Gault equation) <20ml/min: 2.25gram every 6 to 8 hours

Participants would receive the traditional 30-minute intravenous infusion of Piperacillin-Tazobactam after treatment assignment until Piperacillin-Tazobactam was decided to be discontinued by attending physician according to clinical condition and culture sensitivity results.
Control group
Active

Outcomes
Primary outcome [1] 290664 0
The Primary clinical outcome is the 14-day mortality rate.
Timepoint [1] 290664 0
14 days after patient assignment
Secondary outcome [1] 305029 0
In-hospital mortality rate
Timepoint [1] 305029 0
Until the subject discharged from hospital
Secondary outcome [2] 305030 0
Time to defervescence
Timepoint [2] 305030 0
Until the subject experience persistence of temperature below 37.5 degree Celsius for 24 hours.
Secondary outcome [3] 305031 0
Number of days receiving mechanical ventilator support
Timepoint [3] 305031 0
Until the subject weans off mechanical ventilator support.
Secondary outcome [4] 305032 0
Length of intensive care unit (ICU) stay
Timepoint [4] 305032 0
Until the subject discharged from ICU
Secondary outcome [5] 305034 0
Length of hospital stay
Timepoint [5] 305034 0
Until the subject discharged from hospital

Eligibility
Key inclusion criteria
Patients were eligible if they were aged 18 years or older; were hospitalized in an acute medical unit or intensive care unit; either had received a diagnosis of bacterial infection or suffered from neutropenic fever; planned to receive treatment of Piperacillin-Tazobactam for at least 48 hours.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients would be excluded if they are pregnant, had received more than 48 hours of effective antibiotics, as defined by specimen culture sensitivity results, within five days of initiation of extended 4-hour infusion or traditional 30-minute infusions of Piperacillin-Tazobactam; had been receiving other beta-lactam antibiotics concomitantly.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All hospitalized patients would receive a computer generated hospital number, also known as "HN number", in which the assigned method of numbering is not known to the investigators and treating physicians.
Patients carrying a hospital number ended with an even number, excluding the alphabetical letter, would be assigned to the study group whereas patients carrying a hospital number ended with an odd number, excluding the alphabetical letter, would be assigned to the control group.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients carrying a hospital number ended with an even number, excluding the alphabetical letter, would be assigned to the study group whereas patients carrying a hospital number ended with an odd number, excluding the alphabetical letter, would be assigned to the control group.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
A sample size calculation was carried out based on previous retrospective cohort (Raymond J. Yost et al. The Retrospective Cohort of Extended-infusion Piperacillin-Tazobactam (RECEIPT) Study. Pharmacotherapy 2011; 31(8):767-775) demonstrating a significant reduction in mortality from 20.2% to 9.7% for extended 4-hour Piperacillin-Tazobactam infusion. A sample size of 360 was required to provide more than 80% power using a two sided alpha-level of 0.05 to detect a relative risk reduction in mortality rate of 50 percent between the extended 4-hour infusion and traditional 30-minute infusion of Piperacillin-Tazobactam.
Categorical variables were compared using Chi-square test. Continuous variables were compared using Student’s t test or Mann-Whitney U test. A P value of less than 0.05 was considered to indicate statistical significance, and all tests were two-sided. All calculations were performed using SPSS version 16 for Windows.

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 outside Australia
Country [1] 5484 0
Hong Kong
State/province [1] 5484 0
Hong Kong

Funding & Sponsors
Funding source category [1] 288089 0
Self funded/Unfunded
Name [1] 288089 0
Not applicable
Address [1] 288089 0
Not applicable
Country [1] 288089 0
Primary sponsor type
Individual
Name
Fan Sheung Yin
Address
Pharmacy department, G/F, Main Block,
Pamela Youde Nethersole Eastern Hospital
3 Lok Man Road, Chai Wan
Country
Hong Kong
Secondary sponsor category [1] 286811 0
None
Name [1] 286811 0
Not applicable
Address [1] 286811 0
Not applicable
Country [1] 286811 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290013 0
Hong Kong East Cluster Ethics Committee
Ethics committee address [1] 290013 0
Room 133, 2/F, Main Block, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan
Ethics committee country [1] 290013 0
Hong Kong
Date submitted for ethics approval [1] 290013 0
26/07/2013
Approval date [1] 290013 0
27/09/2013
Ethics approval number [1] 290013 0

Summary
Brief summary
Antibiotic resistance and its associated increasing mortality are ever-growing problems in Hong Kong. Infectious Diseases Society of America stated that the optimization of the antimicrobial dosing, based on pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, was an important part of antibiotic stewardship . In view of the growing need to fight against resistant pathogens, piperacillin-tazobactam (Pip-Tazo) extended 4-hour infusion has been catching worldwide attention in the past few years.
Piperacillin-Tazobactam is a widely use broad-spectrum beta-lactam antibiotic in hospitals in Hong Kong for the treatment of bacterial infections. The bactericidal effect of Pip-Tazo is maximized by maintaining the free drug concentration (Cf) above the minimum inhibitory concentration (MIC) for greater than fifty percent of time (T) . PK and PD studies carried out in the past decade on Pip-Tazo’s time-dependent killing (50% CfT>MIC) property had revealed that by extending its infusion time from 30 minutes to 4 hours, the probability of attaining the target (50% CfT>MIC) was highly increased for pathogens with MIC greater than 1mcg/ml , .
Further studies had lent support to the clinical efficacy of Pip-Tazo extended infusion. A retrospective cohort study had shown that the 14-day mortality rate and median duration of hospital stay were significantly reduced for patients who received extended 4-hour infusion of Pip-Tazo compared to those who received intermittent 30-minute infusion for patients with Acute Physiological and Chronic Health Evaluation–II (APACHE II) scores greater than 173. Another retrospective study had also demonstrated significant mortality reduction for extended 4-hour infusion of Pip-Tazo .
To the knowledge of the investigators, there had not been any prospective clinical trial studies carried out on Chinese population on the clinical outcomes of extended 4-hour infusion of Pip-Tazo in comparison to traditional non-extended 30-minute infusion of piperacillin-tazobactam.

It had been expected that the patients receiving extended 4-hour infusion of Pip-Tazo would have a lower 14-day and in-hospital mortality rate, shorter time to defervescence, shorter number of days receiving mechanical ventilator support and length of ICU and hospital stay in comparison to the traditional 30-minute infusion.

The results of this research may guide the future dosing strategy of Pip-Tazo.
Trial website
Trial related presentations / publications
Fan, S.-Y., Shum, H.-P., Cheng, W.-Y., Chan, Y.-H., Leung, S.-Y. M. and Yan, W.-W. (2017), Clinical Outcomes of Extended Versus Intermittent Infusion of Piperacillin/Tazobactam in Critically Ill Patients: A Prospective Clinical Trial.
Pharmacotherapy, 37: 109–119. doi:10.1002/phar.1875
Public notes

Contacts
Principal investigator
Name 43478 0
Ms Fan Sheung Yin
Address 43478 0
Pharmacy Department,
G/F, Main Block,
Pamela Youde Nethersole Eastern Hospital,
3 Lok Man Road, Chai Wan
Country 43478 0
Hong Kong
Phone 43478 0
+85264600823
Fax 43478 0
Email 43478 0
fsy229@ha.org.hk
Contact person for public queries
Name 43479 0
Ms Fan Sheung Yin
Address 43479 0
Pharmacy Department,
G/F, Main Block,
Pamela Youde Nethersole Eastern Hospital,
3 Lok Man Road, Chai Wan
Country 43479 0
Hong Kong
Phone 43479 0
+85264600823
Fax 43479 0
Email 43479 0
fsy229@ha.org.hk
Contact person for scientific queries
Name 43480 0
Ms Fan Sheung Yin
Address 43480 0
Pharmacy Department,
G/F, Main Block,
Pamela Youde Nethersole Eastern Hospital,
3 Lok Man Road, Chai Wan
Country 43480 0
Hong Kong
Phone 43480 0
+85264600823
Fax 43480 0
Email 43480 0
fsy229@ha.org.hk

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