Trial document




drksid header

  DRKS00011023

Trial Description

start of 1:1-Block title

Title

Therapeutic drug Monitoring (TDM) of piperacillin in patients with fever in neutropenia in the course of myelosuppressive cytostatic chemotherapy

end of 1:1-Block title
start of 1:1-Block acronym

Trial Acronym

TARGET-FN

end of 1:1-Block acronym
start of 1:1-Block url

URL of the Trial

[---]*

end of 1:1-Block url
start of 1:1-Block public summary

Brief Summary in Lay Language

Bone-marrow-suppressing chemotherapy in cancer patients results in strongly decreased leukocyte production and enhanced vulnerability to infections. Infections are the predominant cause of treatment-associated mortality in cancer patients receiving chemotherapy. Fever becomes manifest in some 80% of such patients during the phase of bone marrow suppression; in most cases it is considered a sign of systemic infection. Timely administration of broad spectrum antibiotics, especially the combination piperacillin/tazobactam, is recommended and leads in ca. 50% of the cases in stable fever reduction. Non-responsiveness to this therapy can be ascribed in the majority of the patients to sub-optimal antibiotic dosage; this assumption has been confirmed in an own pilot study. However, there are certain concerns of simply increasing the dose of the antibiotic, based on recent evidence pertaining to its untoward effects. Also in view of the unknown nature of the causal pathogen at the time of introduction of the therapy, it appears plausible to use a tailored approach consisting in continuous optimization of the drug dose, thus achieving plasma levels of the drug that are sufficient to suppress symptoms of infection. Dose adjustment will be conducted during the first 3 days upon introduction of antibiotic therapy under consideration of plasma drug levels measured 4 hours following administration.

end of 1:1-Block public summary
start of 1:1-Block scientific synopsis

Brief Summary in Scientific Language

In ca. 80% of the patients undergoing myelosuppressive chemotherapy fever during the phase of neutropenia is considered a typical sign of systemic infection. Infections are the predominant cause of treatment-associated mortality in cancer patients. Besides secondarily increasing mortality, fever during neutropenia is associated with significant increase of in-hospital treatment duration and cost. In the first instance, for the attending physician fever may serve as the only sign of an imminent life-threatening infection. Thus, in view of the present immunosuppression in patients with neutropenia, early introduction of empirical treatment with broad-spectrum antibiotics is indicated. One of the most frequently used combinations is piperacillin/tazobactam (Pip/Taz); however, its use results in stable afebrility in only 50% of the patients. Sub-therapeutic drug plasma levels are considered a possible cause for non-responsiveness to this treatment; this assumption was confirmed in own studies with ICU patients. These data support the view that insufficient dosage might be a cause for the failure of empirical antibacterial therapy with Pip/Taz. While dose escalation appears plausible with regard of the side-effect profile of the drug, recent data indicate that it exerts suppressive effects on the innate immune responsiveness and, thus, might further enhance the susceptibility to secondary infections. Therapeutic drug monitoring (TDM) has a proven record as an individualized method in drug therapy, especially in drugs with a narrow therapeutic index. This approach has been barely examined with regard to penicillins. The antimicrobial effects of beta-lactam-antibiotics are time-dependent; thus, it is recommended to maintain plasma levels above the minimal inhibitory concentration (MIC) over at least 50% of the time interval between successive doses. Lack of knowledge about the causal pathogen at the time of introduction of the therapy also urges to consider achievement of such doses that warrant maintenance of MIC for the most dangerous putative pathogen. Dose optimization by means of individual dosage algorithms based on intermittent drug plasma level determinations are feasible and can be elaborated with a few blood samples. Further benefits of this approach and intended pathogen immunophenotyping consist in avoidance of beta-lactam antibiotic overdosage and further immune system suppression with resultant increased infection vulnerability. Using a multivariate model based on fever recording during neutropenia will minimize time-dependent bias. Finally, the cost effectiveness of TDM-based Pip/Taz dosage will be examined.

end of 1:1-Block scientific synopsis
start of 1:1-Block organizational data

Organizational Data

  •   DRKS00011023
  •   2016/09/02
  •   [---]*
  •   yes
  •   Approved
  •   4897-08/16, Ethikkommission der Friedrich-Schiller-Universität Jena an der Medizinischen Fakultät
end of 1:1-Block organizational data
start of 1:n-Block secondary IDs

Secondary IDs

  •   2016-002388-33 
end of 1:n-Block secondary IDs
start of 1:N-Block indications

Health Condition or Problem studied

  •   B99 -  Other and unspecified infectious diseases
end of 1:N-Block indications
start of 1:N-Block interventions

Interventions/Observational Groups

  •   Therapeutic drug monitoring of piperacillin in patients with fever during neutropenia following myelosuppressive cytostatic chemotherapy. Upon randomization piperacillin/tazobactam (4.0/0.5 g) is injected as a bolus over 15-30 min. Four hours after administration piperacillin plasma level will be measured and the dose adjusted, as follows:
    # Pip plasma level >64 mg/l -- Pip/Taz dosage 3x 4.0/0.5 daily
    # Pip plasma level 48-63 mg/l -- Pip/Taz dosage 4x 4.0/0.5 daily
    Pip plasma level <48 mg/l -- Pip/Taz dosage 3x 8.0/1.0 daily. Dose adjustment will be made during the first 3 days of drug administration; thereafter therapy will continue with the last adjusted dose.
  •   Patients with fever during neutropenia following myelosuppressive cytostatic chemotherapy. Upon randomization piperacillin/tazobactam (4.0/0.5 g) is injected as a bolus over 15-30 min. No Therapeutic drug monitoring will be conducted in the course of treatment.
end of 1:N-Block interventions
start of 1:1-Block design

Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Open (masking not used)
  •   [---]*
  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   IV
  •   No
end of 1:1-Block design
start of 1:1-Block primary endpoint

Primary Outcome

Persistent afebrility (yes/no), defined as absence of fever over 5 consecutive days without changes of the antimicrobial therapy. The proportions of afebrile patients in the groups with and without therapeutic drug monitoring will be compared.

end of 1:1-Block primary endpoint
start of 1:1-Block secondary endpoint

Secondary Outcome

•Mortality over 30 days
•Infection-related mortality over 30 days
•Duration and cumulative dose of antibiotic therapy
•Number of dose adjustments per treatment cycle
•Duration of combined therapy with anti-infectious agents
•Number of in-hospital antibiotic-free days
•Necessity of ICU treatment
•Duration of in-hospital sojourn
•Cost of antibiotic treatment
•Pharmakokinetics (PK) / Pharmakodynamics (PD) - Indices (e.g. antibiotic concentration >4x MIC 100% )
•Number of antibiotic-free days during neutropenia phase
•Infection successfully treated
•Progression to SIRS/Sepsis
•Occurrence of antibiotic-resistant pathogens
•Rate of super-infection with a different pathogen
•Safety (untoward effects)

end of 1:1-Block secondary endpoint
start of 1:n-Block recruitment countries

Countries of Recruitment

  •   Germany
end of 1:n-Block recruitment countries
start of 1:n-Block recruitment locations

Locations of Recruitment

  • Medical Center 
end of 1:n-Block recruitment locations
start of 1:1-Block recruitment

Recruitment

  •   Actual
  •   2016/10/19
  •   208
  •   Monocenter trial
  •   National
end of 1:1-Block recruitment
start of 1:1-Block inclusion criteria

Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
end of 1:1-Block inclusion criteria
start of 1:1-Block inclusion criteria add

Additional Inclusion Criteria

•Fever (defined as 1 episode >38,3°C or 2 episodes >38,0°C within 2 hours) in neutropenia (defined as WBC < 1 Gpt/l or neutrophile granulocytes <0,5Gpt/l) following myelosuppressive chemotherapy
•imminent or ongoing therapy with Piperacillin/Tazobactam (Pip/Taz)
•signed informed consent

end of 1:1-Block inclusion criteria add
start of 1:1-Block exclusion criteria

Exclusion Criteria

•Age < 18 years
•Pregnancy/Breastfeeding
•Women at prolific age without dependable contraception
•Patients unable to consent
•Medical history-documented hypersensitivity toward beta-lactam antibiotics or components of the study drug formulation (Pip/Taz)
•Treatment with Pip/Taz at daily dose >18g within the last 24 hours before randomization
•Participation in another interventional clinical trial
•Prior participation in the current trial (TARGET-FN)
•Impaired liver function (Child-Pugh C)
•Renal failure (eGFR <40ml/min)
•Infectious condition that requires a defined different antibiotic therapy (e.g. endocarditis)
•Life expectancy < 90 days

end of 1:1-Block exclusion criteria
start of 1:n-Block addresses

Addresses

  • start of 1:1-Block address primary-sponsor
    • Universitätsklinikum Jena
    • Bachstraße 18
    • 07740  Jena
    • Germany
    end of 1:1-Block address primary-sponsor
    start of 1:1-Block address contact primary-sponsor
    end of 1:1-Block address contact primary-sponsor
  • start of 1:1-Block address scientific-contact
    • Universitätsklinikum Jena,Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie
    • Ms.  Prof. Dr. med.  Marie  von Lilienfeld-Toal 
    • Am Klinikum 1
    • 07747  Jena
    • Germany
    end of 1:1-Block address scientific-contact
    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
  • start of 1:1-Block address public-contact
    • Universitätsklinikum Jena,Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie
    • Ms.  Prof. Dr. med.  Marie  von Lilienfeld-Toal 
    • Am Klinikum 1
    • 07747  Jena
    • Germany
    end of 1:1-Block address public-contact
    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
end of 1:n-Block addresses
start of 1:n-Block material support

Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Bundesministerium für Bildung und Forschung - Dienstsitz Berlin
    • 10117  Berlin
    • Germany
    end of 1:1-Block address materialSupport
    start of 1:1-Block address contact materialSupport
    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
    end of 1:1-Block address contact materialSupport
end of 1:n-Block material support
start of 1:1-Block state

Status

  •   Recruiting stopped after recruiting started
  •   2018/06/06
end of 1:1-Block state
start of 1:n-Block publications

Trial Publications, Results and other Documents

  • [---]*
end of 1:n-Block publications
* This entry means the parameter is not applicable or has not been set.