Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04647331 |
| Other study ID # |
2019-02886 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2021 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
June 2024 |
| Source |
Uppsala University |
| Contact |
Thomas Tängdén, MD, Phd |
| Phone |
+46708370323 |
| Email |
thomas.grenholm.tangden[@]medsci.uu.se |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Infectious endocarditis (IE) is associated with mortality rates of 10-12%. Adequate
antibiotic therapy is crucial for survival and is administered in high doses due to the
severity of the disease. In most cases, beta-lactam antibiotics (e.g. ampicillin, penicillin
G, cefotaxime or cloxacillin) are employed. A number of patient characteristics, such as age,
body weight, and renal function) influence the pharmacokinetics of these drugs. Yet, the
interindividual variability is poorly understood meaning that a large proportion of patients
are at risk of subtherapeutic or excessive drug concentrations that might result in treatment
failure or side effects, respectively.
In the present study, data will be collected on antibiotic concentrations in patients treated
with beta-lactams for infectious endocarditis as well as patient characteristics and
treatment outcomes. A mathematical model will be developed to determine which patient factors
determine drug pharmacokinetics. Based on this model, predictions will be made by
mathematical simulations on which dosing regimens are optimal for individual patients to
ensure therapeutic and non-toxic drug concentrations. In total, 150 patients will be included
at four University Hospitals in Sweden; Uppsala University Hospital, Sahlgrenska University
Hospital in Gothenburg, Skåne University Hospital in Lund and Karolinska University Hospital
in Stockholm. Following informed consent to participate blood samples will be collected at 6
time-points during a dose interval and then at 3 time-points weekly during the full treatment
episode (maximum 6 weeks).
Description:
Objectives The primary objective of the study is to determine the pharmacokinetics of
beta-lactam antibiotics in patients with infectious endocarditis, and how the pharmacokinetic
profile is associated with various patient factors (e.g. age, body weight, renal function).
Secondary objectives are to descriptively assess potential associations between drug
exposure, pharmacokinetic/pharmacodynamic targets and clinical outcomes.
Inclusion of patients and sample size Patients are prospectively included at the departments
of infectious diseases, internal and acute medicine, cardiology and thoracic surgery at four
University Hospitals in Sweden; Uppsala University Hospital, Sahlgrenska University Hospital
in Gothenburg, Skåne University Hospital in Lund and Karolinska University Hospital in
Stockholm. Potential participants are screened for using the electronic medical records.
Inclusion criteria are as follows: (1) admission at one of the study wards, (2) a diagnosis
of probable or verified infectious endocarditis, (3) treatment with ampicillin, penicillin G,
cefotaxime or cloxacillin and (4) informed written consent to participate in the study. The
following exclusion criteria will be applied: (1) age less than 18 years and (2) ongoing or
planned hemodialysis.
Based on previous research using similar methods, 30 patients per antibiotic substance (total
150 patients) is considered sufficient to develop a robust mathematical model.
Collection of blood samples and patient data Following inclusion, a series of samples will be
taken within one week from start of treatment. Beta-lactams are normally prescribed at 6-8 h
dose intervals. One series of 6 blood samples will be collected at 0, 0,5, 1, 2, 4 and 6 or 8
h (depending on dose interval, prior to next dose) after administration of antibiotics.
Thereafter, samples will be collected once weekly and 0, 3 or 4 (mid-dose interval) and 6 or
8 h (depending on dose interval, prior to next dose).
Information on patient characteristics, including age, body weight, and gender, will be
obtained from the electronic medical records. Further, the results of biomarkers (e.g.
albumin, creatinine, CRP), collected as part of routine practice, will be noted. If not
collected as standard of care, patients will be subject to extra samples to ensure biomarkers
are monitored at least twice weekly.
Clinical outcomes Treatment failure is defined as mortality during antibiotic treatment for
infectious endocarditis or relapse of endocarditis within 6 months after completion of
therapy with isolation of the same pathogens as in the initial episode. Other indicators of
treatment failure include acute surgery for endocarditis, clinical deterioration resulting in
transfer to the ICU, thromboembolic events more than 7 days after initiation of antibiotics
and resistance development of the causative bacteria. The following side effects will be
monitored: deterioration of renal impairment, allergic reaction suspected to be caused by the
antibiotic treatment, Clostridioides difficile enteritis or other suspected side effects
resulting in a shift of therapy to another antibiotic.
Handling of samples and data Blood samples will be stored at -70 degrees Celsius at the
Department of infectious diseases at the respective hospital where the samples have been
collected. The samples will be sent to Sahlgrenska University Hospital, Gothenburg, for
determination of drug concentrations.
Patient names and personal identification numbers will be replaced by a number. Personal data
will be stored at the Department of infectious diseases at the respective hospital where the
patient has been included. Only the responsible researchers will have access to the code key
and be able to link personal information to the individual participants. All information will
be handled in accordance with the General Data Protection Regulation (GDPR) and all analyses
and presentation of data will be performed using anonymous data.
Mathematical modeling and simulations The collected drug concentrations will be analyzed by
non-linear mixed effects modeling using NONMEM. Associations between administered dose and
the measured drug concentration over time will be described (pharmacokinetics). Correlations
with patient characteristics and biomarkers, as well as clinical outcomes in terms of cure,
mortality and documented side effects (pharmacodynamics) will be explored.
