Clinical Trial Results:
In vivo measurement of cefuroxime in subcutaneous and bone tissue using microdialysis
Summary
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EudraCT number |
2013-001138-17 |
Trial protocol |
DK |
Global end of trial date |
12 Jun 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jul 2016
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First version publication date |
20 Jun 2015
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Other versions |
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 |
240583
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Orthopedic Research in Aarhus (v/Kjeld Søballe)
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Sponsor organisation address |
Tage Hansens Gade 2, Aarhus C, Denmark,
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Public contact |
Mikkel Tøttrup, Orthopedic Research in Aarhus, mikkel.tottrup@ki.au.dk
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Scientific contact |
Mikkel Tøttrup, Orthopedic Research in Aarhus, mikkel.tottrup@ki.au.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 |
01 Jun 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Jun 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Jun 2014
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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 |
The objective of this study was to describe and compare plasma, subcutaneous tissue and bone pharmacokinetics of cefuroxime after traditional short-term infusion (STI) and continuous infusion (CI). The primary endpoint is time that the free cefuroxime concentration exceeds the minimal inhibitory concentration (fT>MIC) for the predominant staphylococcus aureus MIC of 1 mg/L. This endpoint is reported as the probability of attaining clinically relevant targets of 65% and 90% fT>MIC over the 8 hour observation period.
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Protection of trial subjects |
All trial subjects were observed by an investigator during administration of cefuroxime and during the subsequent sample collection.
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Background therapy |
- | ||
Evidence for comparator |
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Actual start date of recruitment |
24 Sep 2013
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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: 18
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Worldwide total number of subjects |
18
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EEA total number of subjects |
18
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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) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
3
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From 65 to 84 years |
15
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment began in september 2013 and ended june 2014. All patients were recruited from department of Orthopaedic surgery, Horsens Regional Hospital, Denmark | |||||||||
Pre-assignment
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Screening details |
Competent male patients were offered enrolment in the study if they were scheduled for a total knee replacement. Exclusion criteria included the following: allergy to cefuroxime or vancomycin, on-going treatment with cefuroxime, and clinically reduced renal function. | |||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
The investigators were blinded blinded to the mode of cefuroxime administration during surgical placement of the microdialysis catheters, so that the procedure would not be affected by this knowlegde.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Short-term infusion (STI) | |||||||||
Arm description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min) | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Cefuroxim Fresenius Kabi
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Investigational medicinal product code |
J 01 DC 02
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Other name |
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Pharmaceutical forms |
Powder and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min)
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Arm title
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Continuous infusion (CI) | |||||||||
Arm description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min) | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
Cefuroxim Fresenius Kabi
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Investigational medicinal product code |
J 01 DC 02
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Other name |
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Pharmaceutical forms |
Powder and solvent for concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min)
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Baseline characteristics reporting groups
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Reporting group title |
Short-term infusion (STI)
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Continuous infusion (CI)
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Short-term infusion (STI)
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min) | ||
Reporting group title |
Continuous infusion (CI)
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min) |
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End point title |
Probability of target attainment (for a target of 65% fT > MIC in cancellous bone for a MIC of 1 mg/L) [1] | ||||||||||||
End point description |
Using a non-linear mixed effects regression model with a random patient effect for each of the model parameters, a two-compartment model were fitted to the drug concentration data separately for the different tissues. Monte Carlo simulation was used to determine the probability of target attainment (PTA) for targets of 65% (low target) and 90% fT > MIC (high target) for the observation period of 8 hours, and to estimate the area under the concentration–time curve from 0 to infinity.
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End point type |
Primary
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End point timeframe |
Cefuroxime concentrations were quantified within 6 weeks after sample collection using an ultra high performance liquid chromatography assay.
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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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 90% fT > MIC in cancellous bone for a MIC of 1 mg/L) [2] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 65% fT > MIC in cortical bone for a MIC of 1 mg/L) [3] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 90% fT > MIC in cortical bone for a MIC of 1 mg/L) [4] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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Notes [4] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 65% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L) [5] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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Notes [5] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 90% fT > MIC in subcutaneous tissue for a MIC of 1 mg/L) [6] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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Notes [6] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 65% fT > MIC in free plasma for a MIC of 1 mg/L) [7] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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Notes [7] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Probability of target attainment (for a target of 90% fT > MIC in free plasma for a MIC of 1 mg/L) [8] | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Primary
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End point timeframe |
See the first primary endpoint.
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Notes [8] - 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: Population pharmacokinetic modelling and Monte Carlo Simulations provide probabilities of attaining specified targets (probality of target attainment, PTA). Comparison of PTA between groups are usually not supported by other statistical analyses. |
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No statistical analyses for this end point |
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End point title |
Cancellous bone area under the concentration–time curve from 0 to infinity | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Secondary
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End point timeframe |
See the first primary endpoint.
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No statistical analyses for this end point |
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End point title |
Cortical bone area under the concentration–time curve from 0 to infinity | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Secondary
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End point timeframe |
See the first primary endpoint.
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No statistical analyses for this end point |
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End point title |
Subcutaneous tissue area under the concentration–time curve from 0 to infinity | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Secondary
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End point timeframe |
See the first primary endpoint.
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No statistical analyses for this end point |
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End point title |
Free plasma area under the concentration–time curve from 0 to infinity | ||||||||||||
End point description |
See the first primary endpoint.
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End point type |
Secondary
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End point timeframe |
See the first primary endpoint.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
24 September 2013 until 13 June 2014.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
Eudralex (CT 3) | ||||||||||||||||||||||||||||||||||||
Dictionary version |
10
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Reporting groups
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Reporting group title |
Short-term infusion group
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as STI (over 15 min) | ||||||||||||||||||||||||||||||||||||
Reporting group title |
Continuous infusion
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Reporting group description |
The patients in this arm were given 1,500 mg of cefuroxime (Fresenius Kabi AB, Sweden) intravenously in a peripheral catheter as CI (500 mg as loading dose over 5 min followed by CI of the remaining 1,000 mg over 7 hours and 55 min) | ||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||
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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. | |||
Data were analysed using population pharmacokinetic modelling and Monte Carlo Simulations. It should be noted that other modellers/analysts may come to slightly different results because of different approaches, models and software. |