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Right Dose, Right Now: Model Validation


- candidate number27793
- NTR NumberNTR6690
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR25-aug-2017
- Secondary IDsABR:NL60826.029.17 METc VUmc
- Public TitleRight Dose, Right Now: Model Validation
- Scientific TitleRight Dose, Right Now: Model Validation
- ACRONYM
- hypothesisSepsis is a major and growing problem. In the Netherlands alone, around 15.000 patients are diagnosed with severe sepsis each year. Despite major scientific efforts, including many failed clinical trials mainly focusing on inflammatory mediators and the introduction of care bundles, the mortality rate for severe sepsis still remains unacceptably high at around 30%. This is alarming, especially since the incidence of sepsis continues to increase and now exceeds that of colon cancer, breast cancer and AIDS combined.
Antibiotics are essential for treating sepsis. Their early and appropriate use has repetitively been shown to reduce mortality rates. However, achieving adequate antibiotic exposure in critically ill patients is a major challenge due to markedly different pharmacokinetic (PK) profiles in the critically ill. Nevertheless, doctors still rely on standard antibiotic dosing schemes, that were developed based on data from healthy volunteers and non-critically ill patients. Depending on patient characteristics, clinical course and therapy, this strategy may result in underdosing and/or drug-related toxicity during the course of intensive care treatment.

Therefore, we developed AutoKinetics (AutoK) software. AutoK aims to make use of patient data that is available from the electronic patient records, for example about fluid balance and renal function. Using this data, AutoK is able to give fast and precise dosing advice, using published pharmacokinetic models of any drug. AutoK runs on the computer at the bedside. Thus, advice is readily available, even before treatment is started, and is continuously updated as disease and therapy evolve: true personalized dosing.

We believe that AutoK can improve antibiotic dosing, morbidity and mortality for severe sepsis.
Eventually, we will test AutoK in multicenter clinical trial (Right dose, Right now: randomized clinical trial). We will randomize patients with severe sepsis (n=42 per group, per antibiotic), for antibiotic dosing through AutoK or standard therapy.

This study concerns the validation of existing pharmacometric models which are publicly available from the international literature, using prospectively collected data which is not being collected in the context of regular patient care and / or quality controls and using routinely collected data which has been and is being collected in regular patient care and/or quality control. The core part of this research will consist of validating pharmacometric models of the following antibiotics: Vancomycine, Meropenem, Ceftriaxon, Cefotaxim, Ciprofloxacine, Ceftazidim and in addition, depending on analysis availability, the following antimycotics: anidulafungin, voriconazol and fluconazol. However, we intend to validate pharmacometric models of all relevant antibiotics and antimycotic agents that are being used at the ICU.

The aim of this study is to select the most accurate pharmacometric models.
- Healt Condition(s) or Problem(s) studiedSepsis, Infectious diseases, Antibiotics, Pharmacokinetics, Farmacometrics, Prediction model
- Inclusion criteriaFor the prospective part of this study, the inclusion criteria are:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:
- Age ≥ 18 years
- The patient is receiving antibiotics and/or antimycotic agents to treat an infectious disease.

For the retrospective part of this study the inclusion criteria are:

- The patient has been treated on the Intensive Care unit of the VUmc or OLVG Oost and the patient data has been stored in an electronic patient file (in OLVG from 1999 and VUmc from 2003)
- There is at least 1 relevant pharmacometric outcome measure available (e.g. vancomycine plasma concentration)
- Exclusion criterianone
- mec approval receivedyes
- multicenter trialyes
- randomisedno
- group[default]
- Type[default]
- Studytypeobservational
- planned startdate 16-jun-2017
- planned closingdate31-dec-2019
- Target number of participants500
- InterventionsFor the prospective part of the study we will take an average of six blood samples per patient, per antibiotic/antimycotic.
- Primary outcome Agreement between predicted and observed relevant pharmacometric parameters using Bland-Altman analysis
Percentage of correct first predictions of each pharmacometric model.
Extent to which all relevant pharmacometric goals are being met.
- Secondary outcome-
- Timepoints-
- Trial web sitewww.autokinetics.eu
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES B. van Dijk
- CONTACT for SCIENTIFIC QUERIES B. van Dijk
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
ZonMw
- Publications
- Brief summarySepsis is a major and growing problem. In the Netherlands alone, around 15.000 patients are diagnosed with severe sepsis each year. Despite major scientific efforts, including many failed clinical trials mainly focusing on inflammatory mediators and the introduction of care bundles, the mortality rate for severe sepsis still remains unacceptably high at around 30%. This is alarming, especially since the incidence of sepsis continues to increase and now exceeds that of colon cancer, breast cancer and AIDS combined.
Antibiotics are essential for treating sepsis. Their early and appropriate use has repetitively been shown to reduce mortality rates. However, achieving adequate antibiotic exposure in critically ill patients is a major challenge due to markedly different pharmacokinetic (PK) profiles in the critically ill. Nevertheless, doctors still rely on standard antibiotic dosing schemes, that were developed based on data from healthy volunteers and non-critically ill patients. Depending on patient characteristics, clinical course and therapy, this strategy may result in underdosing and/or drug-related toxicity during the course of intensive care treatment.

Therefore, we developed AutoKinetics (AutoK) software. AutoK aims to make use of patient data that is available from the electronic patient records, for example about fluid balance and renal function. Using this data, AutoK is able to give fast and precise dosing advice, using published pharmacokinetic models of any drug. AutoK runs on the computer at the bedside. Thus, advice is readily available, even before treatment is started, and is continuously updated as disease and therapy evolve: true personalized dosing.

We believe that AutoK can improve antibiotic dosing, morbidity and mortality for severe sepsis.
Eventually, we will test AutoK in multicenter clinical trial (Right dose, Right now: randomized clinical trial). We will randomize patients with severe sepsis (n=42 per group, per antibiotic), for antibiotic dosing through AutoK or standard therapy.

This study concerns the validation of pharmacometric models using prospectively collected data which is not being collected in the context of regular patient care and / or quality controls and using routinely collected data which has been and is being collected in regular patient care and/or quality control.

The aim of this study is to select the most accurate pharmacometric models.
- Main changes (audit trail)
- RECORD25-aug-2017 - 21-sep-2017


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