E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients admitted with sepsis of unknown origin, suspected urinary origin or suspected abdominal origin |
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E.1.1.1 | Medical condition in easily understood language |
Patients admitted with sepsis of unknown origin, suspected urinary origin or suspected abdominal origin |
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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 |
To determine the impact of a treatment strategy consisting of cefuroxime + aminoglycoside as first-choice therapy compared to a strategy of ceftriaxone or cefuroxime monotherapy as first-choice therapy on 30-day all-cause mortality in patients with community-onset sepsis of unknown origin, suspected urinary origin, or suspected abdominal origin. |
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E.2.2 | Secondary objectives of the trial |
Secondary outcomes include duration of IC and hospital admission, quality of life, nephrotoxicity, ototoxicity and costs. In a cost-effectiveness analysis we will determine the costs per quality-adjusted life year gained. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Active Follow-up Subset (integrated in the mainstudy protocol): To determine the effect of cefuroxime + aminoglycoside as first-choice therapy compared to ceftriaxone or cefuroxime monotherapy as first-choice therapy in this population on: • Quality of life. • 1 year mortality • Duration of absenteeism • Health care cost per quality-adjusted life year • Societal costs per quality-adjusted life year • Nephrotoxicity according to the The Kidney Disease: Improving Global Outcomes (KDIGO) criteria. • Recovery of renal function in patients with acute renal failure. • Subjective hearing loss.
Pharmacokinetics/pharmacodynamics (integrated in the mainstudy protocol): • To define the association between attained PK/PD index of empirical sepsis treatment with cefuroxime, ceftriaxone, gentamicin and/or tobramycin in the first 48 hours of treatment and 30-day mortality and other clinical outcomes such as renal toxicity and length of hospital stay in patients with community-acquired sepsis • To define population pharmacokinetic characteristics of cefuroxime, ceftriaxone, gentamicin and tobramycin in patients with community-acquired sepsis, including risk factors for not reaching the PK/PD target, in order to design future trials on optimized empirical antibiotic dosing in sepsis • To assess and compare attained PK/PD indices of patients sepsis empirically treated with cefuroxime plus aminoglycoside versus ceftriaxone or cefuroxime monotherapy . • To assess and compare attained PK/PD indices of patients empirically treated with gentamicin versus tobramycin. • To assess if there is a difference in outcomes calculating PK/PD indices based on bacterial ecological cutoff minimally inhibitory concentration (ECOFF) versus MIC based on broth microdilution (BMD).
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E.3 | Principal inclusion criteria |
1) Age >= 18 years 2) Presenting to the ER 3) Suspicion of bacterial infection of unknown origin, primary suspected urinary origin or primary suspected abdominal origin. a. The working diagnosis set by the ER physician must state one of these three origin or ‘sepsis’ without mentioning a suspected focus b. If there is no working diagnosis noted, the differential diagnosis should be assessed. If the differential diagnosis consist of urinary or abdominal infections only, a patient can participated in the study. c. If the differential diagnosis is unclear, very wide (for example: Infection dd urinary tract infection dd pneumonia dd erysipelas dd abdominal focus) or clear, but mentions other origins besides urinary or abdominal, the local PI must be consulted (preferably within 3 days after admission). The PI determines whether patient should be included, depending on how likely a specific differential diagnosis is. If unclear, or very likely urological or abdominal, the patient can be included. 4) National Early Warning Score (NEWS) or Modified Early Warning Score (MEWS) ≥ 5. 5) Requiring intravenous antibiotic treatment and hospitalization. |
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: 1) Working diagnosis at the ER of pneumonia. 2) Chemotherapy induced neutropenia as this is considered a separate entity in the guidelines. 3) Pre-existing renal failure defined as a GFR < 30, due to a relative contra-indication for aminoglycosides. 4) Allergy for cephalosporins or aminoglycosides, known prior to the start of treatment. 5) Indication for empirical coverage of ESBL-producing gram-negative bacteria according to the Dutch sepsis guidelines, i.e. known colonization or infection with ESBL-producing gram-negative bacteria in the prior year. |
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E.5 End points |
E.5.1 | Primary end point(s) |
30-day all-cause mortality defined as mortality within 30 calendar days of the day of initial presentation to the ER, starting at day 0. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• Duration of intravenous antibiotic treatment in calendar days and hours • Time to switch to oral treatment in calendar days and hours • Duration of hospitalization in calendar days • ICU admission, length of ICU stay, mechanical ventilation • ICU admission in patients who are not directly admitted to the ICU • Complications during hospital admission possibly related to the disease or treatment (see Table 4) • Nephrotoxicity requiring dialysis • Hospital re-admission within 30 days of initial hospitalization • Failure of treatment defined as switch of antibiotic treatment because patient is not improving clinically under current policy or because cultures have shown a pathogen that is not covert by the current antibiotic treatment.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
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 | Yes |
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 | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Cluster-randomized cross-over trial |
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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 | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
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 | Yes |
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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |