Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia

Study Overview
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Brief Summary
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The purpose of this study was to compare the efficacy and safety of ceftobiprole medocaril versus a comparator in the treatment of patients with complicated Staphylococcus aureus bacteremia (SAB).

Detailed Description
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Patients were randomized 1:1 to ceftobiprole or the comparator regimen. Randomization was stratified by study site, dialysis status, and prior antibacterial treatment use within 7 days before randomization. The three phases of the study were: Screening assessments of up to 72 hours prior to randomization Randomization and subsequent active treatment with intravenous (i.v.) study drug (ceftobiprole or daptomycin ± aztreonam). Post-treatment, comprising an end of trial (EOT) visit (within 72 hours of last study-drug administration), Day 35 (± 3 days), Day 42 (± 3 days), and a post-treatment evaluation (PTE) visit on Day 70 (± 5 days) post-randomization.

Official Title
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A Randomized, Double-blind, Multi-center Study to Establish the Efficacy and Safety of Ceftobiprole Medocaril Compared to Daptomycin in the Treatment of Staphylococcus Aureus Bacteremia, Including Infective Endocarditis

Conditions
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Staphylococcus Aureus Bacteremia

Intervention / Treatment
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* Drug: Ceftobiprole medocaril
* Drug: Daptomycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥ 18 years of age Staphylococcus aureus bacteremia (SAB), based on at least one positive blood culture obtained within the 72 h prior to randomization At least one of the following signs or symptoms of bacteremia: fever (e.g.≥ 38 °C/100.4 °F measured orally) white blood cell count > 10,000 or < 4,000 cells/µL, or > 10% immature neutrophils (bands) tachycardia (heart rate > 90 bpm) hypotension (systolic blood pressure < 90 mmHg) At least one of the following: SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis Persistent SAB Definite native-valve right-sided infective endocarditis by Modified Duke's Criteria Other forms of complicated SAB Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis) Epidural or cerebral abscess Other inclusion criteria have been applied Exclusion Criteria: Treatment with potentially effective (anti-staphylococcal) systemic antibacterial treatment for more than 48 h within the 7 days prior to randomization; Exception: Documented failure of bloodstream clearance Bloodstream or non-bloodstream concomitant infections with Gram-negative bacteria that are known to be non-susceptible to either ceftobiprole or aztreonam Left-sided infective endocarditis Prosthetic cardiac valves or valve support rings, cardiac pacemakers, automatic implantable cardioverter-defibrillator, or left-ventricular assist devices Community- or hospital-acquired pneumonia Opportunistic infections within 30 days prior to randomization, where the underlying cause of these infections is still active Requirement for continuous renal-replacement therapy Women who are pregnant or nursing Other exclusion criteria have been applied

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftobiprole medocaril<br>Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) | Drug: Ceftobiprole medocaril<br>* Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) as a 2 h infusion<br>|
| Active Comparator: Daptomycin<br>Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards), with or without aztreonam | Drug: Daptomycin<br>* Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit | Comparison of overall success rates in the mITT population Overall success at PTE for the mITT population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization. No new metastatic foci or complications of the SAB infection. Resolution or improvement of SAB-related clinical signs and symptoms. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus) | PTE visit on Day 70 (± 5 days) post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With or Without Overall Success at the PTE Visit in the CE Population | Comparison of overall success rates in the Clinical Evaluable (CE) population Overall success at PTE for the CE population was defined as all of the following criteria being met (Responder): Patient alive at Day 70 (± 5 days) post-randomization. No new metastatic foci or complications of the SAB infection. Resolution or improvement of SAB-related clinical signs and symptoms. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus) | At PTE visit on Day 70 (± 5 days) post-randomization | 
| Number of Patients With Microbiological Eradication at the PTE Visit | Comparison of microbiological eradication rates in the mITT population. Microbiological eradication rate was defined as a negative blood culture for S. aureus during study treatment and another negative blood culture during the follow up period up to PTE. | At PTE visit on Day 70 (± 5 days) post-randomization | 
| All-cause Mortality at the PTE Visit | Comparison of all-cause mortality rates in the mITT population | At PTE visit on Day 70 (± 5 days) post-randomization | 
| Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 | Comparison of complication rates in the mITT population defined by number of patients with development of new metastatic foci or other complications of SAB after Day 7 | Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days) | 
| Time to Staphylococcus Aureus Bloodstream Clearance | Time-to-event in the mITT Bloodstream clearance was defined as two consecutive study days with blood-culture-negative assessments for S. aureus, without any subsequent S. aureus relapse or reinfection | Up to 6 weeks post-randomization | 
| Number of Patients With or Without Adverse Events (AEs) | Treatment-emergent adverse events in the safety population | AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ceftobiprole, daptomycin, Staphylococcus aureus, Bacteremia, bloodstream infection