Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia

Phase 3

Completed

• Conditions: Staphylococcus Aureus Bacteremia
• Interventions: Drug: Ceftobiprole medocaril; Drug: Daptomycin

• Registration Number: NCT03138733
• Lead Sponsor: Basilea Pharmaceutica

Brief Summary

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

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:

1. Screening assessments of up to 72 hours prior to randomization

2. Randomization and subsequent active treatment with intravenous (i.v.) study drug (ceftobiprole or daptomycin ± aztreonam).

3. 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.

Study Timeline

• Study First Submitted: 2017-04-27
• Study First Submitted QC: 2017-04-29
• Study First Posted: 2017-05-03
• Study Start: 2018-08-26
• Primary Completion: 2022-03-11
• Study Completion: 2022-03-11
• Results First Submitted: 2023-03-06
• Results First Submitted QC: 2023-04-12
• Results First Posted: 2023-05-06
• Status Verified: 2023-10
• Last Update Submitted: 2023-10-17
• Last Update Posted: 2023-11-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 390

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:

  1. fever (e.g.≥ 38 °C/100.4 °F measured orally)
  2. white blood cell count > 10,000 or < 4,000 cells/µL, or > 10% immature neutrophils (bands)
  3. tachycardia (heart rate > 90 bpm)
  4. hypotension (systolic blood pressure < 90 mmHg)

• At least one of the following:

  1. SAB in patients undergoing chronic intermittent hemodialysis or peritoneal dialysis
  2. Persistent SAB
  3. Definite native-valve right-sided infective endocarditis by Modified Duke's Criteria
  4. Other forms of complicated SAB
  5. Osteomyelitis (including vertebral, sternal, or long-bone osteomyelitis)
  6. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ceftobiprole medocaril	Ceftobiprole medocaril	Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril)
Daptomycin	Daptomycin	Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards), with or without aztreonam

Primary Outcome Measures

Name	Time	Method
Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit	PTE visit on Day 70 (± 5 days) post-randomization	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): 1. Patient alive at Day 70 (± 5 days) post-randomization.; 2. No new metastatic foci or complications of the SAB infection.; 3. Resolution or improvement of SAB-related clinical signs and symptoms.; 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)

Secondary Outcome Measures

Name	Time	Method
Number of Patients With or Without Overall Success at the PTE Visit in the CE Population	At PTE visit on Day 70 (± 5 days) post-randomization	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): 1. Patient alive at Day 70 (± 5 days) post-randomization.; 2. No new metastatic foci or complications of the SAB infection.; 3. Resolution or improvement of SAB-related clinical signs and symptoms.; 4. Two negative blood cultures for S. aureus (without any subsequent positive blood culture for S. aureus)
Number of Patients With Microbiological Eradication at the PTE Visit	At PTE visit on Day 70 (± 5 days) post-randomization	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.
All-cause Mortality at the PTE Visit	At PTE visit on Day 70 (± 5 days) post-randomization	Comparison of all-cause mortality rates in the mITT population
Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7	Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days)	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
Time to Staphylococcus Aureus Bloodstream Clearance	Up to 6 weeks post-randomization	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
Number of Patients With or Without Adverse Events (AEs)	AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days)	Treatment-emergent adverse events in the safety population

Trial Locations

Locations (60)

eStudy Site - Chula Vista - PPDS; 🇺🇸 Chula Vista, California, United States

Triple O Medical Services Inc; 🇺🇸 West Palm Beach, Florida, United States

Mercury Street Medical Group; 🇺🇸 Butte, Montana, United States

eStudy Site - Las Vegas - PPDS; 🇺🇸 Las Vegas, Nevada, United States

Remington Davis Inc.; 🇺🇸 Columbus, Ohio, United States

Central Hospital de San Isidro Melchor Posse; 🇦🇷 Buenos Aires, Argentina

Medical Institute Platense SA; 🇦🇷 La Plata, Argentina

British Sanatorium SA; 🇦🇷 Rosario, Argentina

University Multiprofile Hospital for Active Treatment "Eurohospital Plovdiv", Plovdiv, Intensive Care Clinic; 🇧🇬 Plovdiv, Bulgaria

University Multiprofile Hospital for Active Treatment 'Kanev', Ruse, Department of General, Purulent-Septic, Pediatric and One Day Surgery; 🇧🇬 Ruse, Bulgaria

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