Clinical Trial Results:
Pharmacokinetics and pharmacodynamics of Piperacillin-Tazobactam (PT) in pediatric oncology patients with fever and neutropenia
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Summary
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EudraCT number |
2017-004281-10 |
Trial protocol |
DK |
Global end of trial date |
30 Jun 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Nov 2021
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First version publication date |
04 Nov 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PT/11/2017
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Aarhus University Hospital
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Sponsor organisation address |
Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
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Public contact |
Sabine Frølich Maarbjerg, Department of Pediatric Oncology, Aarhus University Hospital, Skejby, sabine.froelich@midt.rm.dk
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Scientific contact |
Sabine Frølich Maarbjerg, Department of Pediatric Oncology, Aarhus University Hospital, Skejby, 0045 22165904, sabine.froelich@midt.rm.dk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Feb 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
30 Jun 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
With the overall objective of optimizing the dosing regimen of empirical piperacillin-tazobcctam treatment in pediatric febrile neutropenia (FN), we investigated whether continuous piperacillin-tazobcctam infusions provide antibiotic concentrations associated with maximal activity and optimal target attainment.
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Protection of trial subjects |
The trial was conducted in accordance with the ethical standards described in the declaration of Helsinki.
Approvals were obtained from the Central Denmark Region Committee on Health Research Ethics, the Danish Data Protection Agency and the Danish Medicines Agency. Written informed consent was obtained from both parents or legal guardians. Children aged 15 to 17 years were allowed to give written informed consent for themselves, in close collaboration with their parents or legal guardians.
Experienced nurses were handling the blood sampling and administration of study drug. Furthermore, all information regarding the trial was given by study nurses or doctors with large pediatric experience. Data was registered, saved and managed using REDCap (Research Electronic Data Capture), hosted at the Department of Clinical Medicine, Aarhus University. REDCap is a secure, web-based software platform designed to support data capture for research studies.
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Background therapy |
As standard empirical therapy of pediatric FN, piperacillin-tazobactam (300 mg/kg/day) was prescribed as intermittent administration every eight hours by the treating physician. After study enrollment, the study participants received a piperacillin-tazobactam loading bolus (100 mg/kg) followed by continuous infusion of piperacillin-tazobactam (300 mg/kg/day) at a fixed rate over 24 hours by a CADD®-Solis VIP infusion pump. Blood sampling points covered peak concentration immediately after loading dose and prior to continuous infusion -initiation (2-30 minutes), distribution phase (0.5-1.5 hours), and Css (12-24 hours). | ||
Evidence for comparator |
Consensual PK/PD targets required for maximum efficacy of ��-lactams in critically ill and neutropenic children remain to be estasblished. For piperacillin, antibacterial effect is attained with a free drug concentration above MIC for 40%–70% of the time. However, a growing body of evidence recommends the use of higher PK/PD targets of 100% fT>MIC or even up to 100% fT>4-6xMIC to maximize the bactericidal effect and compensate for the reduced immunological response and limited post-antibiotic effect in neutropenic patients. Subsequently, the following PK/PD targets were evaluated in this trial: (1) 100% fT>MIC and (2) 50% fT>4xMIC. Although these targets are considered quite stringent, several other studies also evaluated these targets, and they are increasingly used among critically ill and neutropenic patients. The PK/PD targets were evaluated in relation to the piperacillin MIC spectrum of blood stream infections in children with cancer at our institution, and the EUCAST MIC breakpoint for Pseudomonas aeruginosa (16 mg/L). In terms of antimicrobial susceptibility, P. aeruginosa represents a worst-case scenario and an increase in resistant P. aeruginosa strains has been reported during the last decades. Accordingly, it is recommended that empirical management of pediatric FN contain antipseudomonal coverage. | ||
Actual start date of recruitment |
01 Aug 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 76
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Worldwide total number of subjects |
76
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EEA total number of subjects |
76
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
4
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Children (2-11 years) |
44
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Adolescents (12-17 years) |
28
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Study participants were recruited when they were admitted with FN and was prescribed piperacillin-tazobactam. Written informed consent was obtained from both parents or legal guardians. Children aged 15 to 17 years were allowed to give written informed consent for themselves, in close collaboration with their parents or legal guardians. | |||||||||
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Pre-assignment
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Screening details |
Medical assessment | |||||||||
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Period 1
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Period 1 title |
Intervention (Overall study period) (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
OBS!!!!!!! We have added an extra arm, due the system that can not manage single arm studies. The duplet arm contains identical information as the intervention arm. A total of 38 patients were included.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Total study population | |||||||||
Arm description |
Single-arm study | |||||||||
Arm type |
Total study population | |||||||||
Investigational medicinal product name |
Piperacillin-tazobactam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
As standard care, intravenous piperacillin-tazobactam was prescribed at 300 mg/kg/day and administered intermittently every eight hours. After study enrollment, eligible patients received an intravenous 2-5 minutes piperacillin-tazobactam loading dose of 100 mg/kg (not subtracted from the total daily dose) followed by continuous infusion of 300 mg/kg/day (piperacillin component, maximum of 16 000 mg/day) at a fixed rate over 24 hours.
A supplemental loading dose of 100 mg/kg (maximum four doses per day) was administered in case of a discontinued infusion for longer than 30 minutes.
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Arm title
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Total study population - duplet | |||||||||
Arm description |
Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Piperacillin-tazobactam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
As standard care, intravenous piperacillin-tazobactam was prescribed at 300 mg/kg/day and administered intermittently every eight hours. After study enrollment, eligible patients received an intravenous 2-5 minutes piperacillin-tazobactam loading dose of 100 mg/kg (not subtracted from the total daily dose) followed by continuous infusion of 300 mg/kg/day (piperacillin component, maximum of 16 000 mg/day) at a fixed rate over 24 hours.
A supplemental loading dose of 100 mg/kg (maximum four doses per day) was administered in case of a discontinued infusion for longer than 30 minutes.
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Baseline characteristics reporting groups
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Reporting group title |
Total study population
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Reporting group description |
Single-arm study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Total study population - duplet
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Reporting group description |
Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Total study population
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Reporting group description |
Single-arm study | ||
Reporting group title |
Total study population - duplet
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Reporting group description |
Duplet - total study population. This arm is made since the system does not accept single arm studies. This arm contains identical information. | ||
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End point title |
Attainment of the target of 100% fT>MIC for the P. aeruginosa breakpoint [1] | ||||||||||||||||||
End point description |
Attainment of the target of 100% fT>MIC for the P. aeruginosa breakpoint
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End point type |
Primary
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End point timeframe |
Entire study period
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Probability of target attainment of the target of 50% (100% for continuous infusion) fT>4xMIC [2] | ||||||||||||||||||
End point description |
Probability of target attainment of the target of 50% (100% for continuous infusion) fT>4xMIC
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End point type |
Primary
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End point timeframe |
Entire study period
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Predictions of median steady state concentrations (95% percentiles) for continuous infusion of 300 mg/kg/day [3] | ||||||||||||
End point description |
Predictions of median steady state concentrations (95% percentiles) for continuous infusion of 300 mg/kg/day
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End point type |
Primary
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End point timeframe |
Entire study period
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The manuscript (containing statistics information) will be oploaded as soon as it is published. |
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
Time frame for reporting adverse events: 1 August 2018 - 30 June 2020.
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Assessment type |
Non-systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
Product resume | ||
Dictionary version |
06022021
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| Frequency threshold for reporting non-serious adverse events: 5% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events were reported. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Samples were collected in blood, which may represent an imprecise surrogate of drug concentrations at the infective site. To allow a further refinement of the dosing regimen for the youngest children, this age group should contain more children. | |||
