| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| All patients given standard of care intravenous therapy of the studied antibiotics will be screened against the inclusion criteria. Two groups are included: Group A (septic patients with organ dysfunction defined as SOFA >2) and Group B (control group of non-septic patients without organ dysfunction defined as SOFA <2). We will include 4 Group C healthy volunteers, which will receive both meropenem and linezolid. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients and controls who receive the studied drugs. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objectives
- Identify host factors that predict the unbound plasma to tissue ratio of the selected antibiotics in critically ill patients.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives
- Determine whether antibiotic dosing for critically ill patients achieves the concentrations associated with maximal activity.
- Correlate the tissue penetration with both biomarkers of the host immune response and with clinical outcomes.
- Comparison of observed antibiotic pharmacokinetics/pharmacodynamics indices with the clinical outcome of therapy.
- Characterize the relationship between PK TDM, MIC and biomarker profiles in patients.
- Determine the PB of different antibiotics.
- Identify optimal model-based dosing targets implementable in TDM routines, which include PK, MIC and host response profiles.
- Safety and tolerability of the included antibiotics.
- Development of a PK model and clinical scoring system predicting tissue/plasma ratio of the drug exposure in patients with systemic critical infections (sepsis).
- Description of the population pharmacokinetics of the individual antibiotics in ICU patients.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Group A (septic patients with organ dysfunction defined as SOFA >2):
• ≥ 18 years old
• SOFA >2 at study inclusion
• Therapy with one of the chosen antibiotics via continuous or intermittent dosing regimen (indication at the discretion of the treating physicians) for at least 2 days at time of inclusion.
• If possible written informed consent obtained from the patient.
• Retrospectively given signed and dated informed consent – patients may be unconscious during the study duration making prior approval impossible. However, as most of the procedures based on this study represents a therapeutic approach, except for the microdialysis and additional samples, informed consent of the patients will be inquired as soon as they regain the ability to fully understand the given information.
Group B (control group of non-septic patients without organ dysfunction defined as SOFA <2):
• ≥ 18 years old
• SOFA <2 at study inclusion
• Therapy with one of the chosen antibiotics via continuous or intermittent dosing regimen (indication at the discretion of the treating physicians) for at least 2 days at time of inclusion.
• If possible, written informed consent obtained from the patient.
• Retrospectively given signed and dated informed consent – patients may be unconscious during the study duration making prior approval impossible. However, as most of the procedures based on this study represents a therapeutic approach, except for the microdialysis and additional samples, informed consent of the patients will be inquired as soon as they regain the ability to fully understand the given information.
Group C (control group of healthy volunteers)
• Healthy subjects aged 18 to 55
• Good state of health (mentally and physically)
• Body mass index within a range of 17.5 to 32 kg/m²
• No regular medication within the last 2 weeks prior to the first study day
• A signed and dated written informed consent form
• The subject is fully capable to understand and willingly to comply with the protocol requirements, timetables, instructions and protocol-stated restrictions
• Negative serology (human immunodeficiency virus, hepatitis Bs-Ag and C-Ab) at screening
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| E.4 | Principal exclusion criteria |
Group A and B:
• Known allergy or hypersensitivity against the study drug.
• Any disease (investigator´s judgement) considered relevant for the proper performance of the study (for example autoimmune diseases; severe systemic inflammation caused by other diseases; or chronic diseases requiring immunomodulation therapy).
• Requiring hemofiltration or hemodialysis.
• Pregnancy.
• Antibiotic cessation before the first blood sample collection.
• Non-stable dose for the previous 24 hours.
• Positive serology for hepatitis or HIV.
• Patients with thrombocytopenia associated with a significant risk of bleeding (< 50 G/L) or a disorder of plasmatic coagulation (DIC, factor deficiency)
• Any disease considered relevant for proper performance of the study, or risks to the patient, at the discretion of the investigator.
• Other factors that preclude study participation in the opinion of the investigator.
Group C:
• Pregnancy
• Women of childbearing potential and men who are not employing contraceptive measures or abstain from sexual contact until one week after the final examination
• Any acute or chronic illness or clinically relevant (Investigator’s judgement) abnormality identified on the screening medical assessment, laboratory tests or ECG, unless in the opinion of the Investigator it will not interfere with the study procedures, affect the outcome of the study or compromise the safety of the subject
• Laboratory or clinical signs of any clinically relevant coagulation disorder
• Any contraindication against administration of any active or inactive ingredients of the designated study medication including known allergic or anaphylactic reactions and history of hypersensitivity reactions
• Impaired renal function with a creatinine clearance of ≤ 90 mL/min (Cockroft gault calculated)
• Ongoing smoking of greater than five cigarettes (or equivalent) per day.
• Alcohol abuse (more than 2 glasses of either a small beer, 1/8 L wine or 2 cL spirits per day)
• Drug abuse
• Participation in a trial with any drug within 30 days or five half-lives (whichever is longer) before the start of the study.
• Any other reason that the Investigator considers making the subject unsuitable to participate
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PRIMARY ENDPOINTS
Correlating of the plasma to tissue penetration ratio (determined as AUCSC tissue/AUCplasma-unbound for microdialysis over the investigated dosing interval and as CELF/Cplasma-unbound for ELF at the time of the BAL procedure) with the investigated selected biomarkers described below.
Measurements for the primary endpoints:
PK endpoints
For plasma, BAL and subcutaneous tissue:
- Determination of the PK of the included antibiotics in lung, subcutaneous tissue and plasma in critically ill patients
o Area under the time-concentration curve of the unbound drug concentrations from time point zero to last observed concentration (AUC0-n) (only for plasma and subcutis)
o Maximum post-dose drug concentration in the respective investigated compartment (Cmax)
o Mean (or average) concentration that a drug achieves in the respective investigated compartment (Caverage)
o Time to reach maximum drug concentration in the respective investigated compartment (Tmax)
o Half-life (T1/2)
o Subcutaneous tissue to plasma ratios (AUCSC/AUCplasma, Cmax SC/Cmax plasma)
o ELF to plasma ratios (CBAL/C plasma)
Only for plasma:
- Volume of distribution (Vd)
- Clearance (Cl)
- Protein binding (PB)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of study day and final examination |
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| E.5.2 | Secondary end point(s) |
SECONDARY ENDPOINTS
Clinical endpoints
- Severity and predicted mortality: APACHE II and SAPS II scores at study day
- Organ dysfunction: SOFA score at study day
- Length of stay in ICU (days)
- Length of hospitalization (days)
- ICU survival
- 7-day all-cause mortality
- Treatment failure: discontinuation of the antibiotic regimen for reasons other than cure, de-escalation or streamlining; a dose increase or addition of another antibiotic beyond 48 hours of treatment; the requirement of an additional source control procedure performed >48 hours post-initiation of antibiotic treatment; in-hospital death of any cause; or readmission due to recurrence of the same infection within 30 days of discharge.
- Clinical cure: patient alive, no fever, symptoms attributed to the focus of infection have resolved and negative cultures.
Microbiological endpoints
- Minimum inhibitory concentration (MIC): lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
PK/PD endpoints
- PK/PD ratios. Attainment of PK/PD targets and comparison to currently established/discussed breakpoints. Where available, the MIC of the known pathogen is provided by the local microbiology laboratory.
- Probability of target attainment (PTA) analysis for different pathogens
Biomarker endpoints
- Determination of the concentration of the selected biomarkers
TOLERABILITY / SAFETY ENDPOINTS
Safety and tolerability of the antibiotics will be collected to define any adverse drug reaction (clinically observed, hematological or biochemical) that is reported by the clinical staff at the participating ICUs that is suspected as being caused by any of the study antibiotics. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of study day and final examination |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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