ANZCTR - Registration

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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]

Nil

Universal Trial Number (UTN)

U1111-1148-8097

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Infection

Condition category

Condition code

Infection

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]

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]

The Primary clinical outcome is the 14-day mortality rate.

Timepoint [1]

14 days after patient assignment

Secondary outcome [1]

In-hospital mortality rate

Timepoint [1]

Until the subject discharged from hospital

Secondary outcome [2]

Time to defervescence

Timepoint [2]

Until the subject experience persistence of temperature below 37.5 degree Celsius for 24 hours.

Secondary outcome [3]

Number of days receiving mechanical ventilator support

Timepoint [3]

Until the subject weans off mechanical ventilator support.

Secondary outcome [4]

Length of intensive care unit (ICU) stay

Timepoint [4]

Until the subject discharged from ICU

Secondary outcome [5]

Length of hospital stay

Timepoint [5]

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

Sex

Both males and females

Can healthy volunteers participate?

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

15/10/2013

Actual

1/12/2013

Date of last participant enrolment

Anticipated

Actual

31/08/2015

Date of last data collection

Anticipated

Actual

30/09/2015

Sample size

Target

360

Accrual to date

Final

367

Recruitment outside Australia

Country [1]

Hong Kong

State/province [1]

Hong Kong

Funding & Sponsors

Funding source category [1]

Self funded/Unfunded

Name [1]

Not applicable

Address [1]

Not applicable

Country [1]

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]

None

Name [1]

Not applicable

Address [1]

Not applicable

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Hong Kong East Cluster Ethics Committee

Ethics committee address [1]

Room 133, 2/F, Main Block, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Road, Chai Wan

Ethics committee country [1]

Hong Kong

Date submitted for ethics approval [1]

26/07/2013

Approval date [1]

27/09/2013

Ethics approval number [1]

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

Ms Fan Sheung Yin

Address

Pharmacy Department,
G/F, Main Block,
Pamela Youde Nethersole Eastern Hospital,
3 Lok Man Road, Chai Wan

Country

Hong Kong

Phone

+85264600823

Fax

fsy229@ha.org.hk

Contact person for public queries

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

Phone

+85264600823

Fax

fsy229@ha.org.hk

Contact person for scientific queries

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

Phone

+85264600823

Fax

fsy229@ha.org.hk

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Clinical Outcomes of Extended Versus Intermittent Infusion of Piperacillin/Tazobactam in Critically Ill Patients: A Prospective Clinical Trial.	2017	https://dx.doi.org/10.1002/phar.1875

N.B. These documents automatically identified may not have been verified by the study sponsor.

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