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)

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

Giuliano Isontina University Health Authority; 🇮🇹 Trieste, Italy

The Baruch Padeh Medical Center; 🇮🇱 Poriyya 'Illit, Israel

Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital; 🇺🇦 Dnipro, Ukraine

Dnipropetrovsk City Multispecialty Clinical Hospital #4; 🇺🇦 Dnipro, Ukraine

Central Friuli University Healthcare Company; 🇮🇹 Udine, Italy

Istanbul Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital; 🇹🇷 Istanbul, Turkey

N.I. Pirogov City Clinical Hospital #1; 🇷🇺 Moscow, Russian Federation

Hospital del Mar, Department of Intensive Care; 🇪🇸 Barcelona, Spain

Mediclinic Victoria - Practice of R Moodley and MI Sarwan; 🇿🇦 Tongaat, South Africa

General University Hospital Gregorio Maranon, Infectious Diseases / Internal Medicine; 🇪🇸 Madrid, Spain

Ivano-Frankivsk Regional Clinical Hospital; 🇺🇦 Ivano-Frankivs'k, Ukraine

University Hospital Ramon y Cajal, Department of Infectious Diseases; 🇪🇸 Madrid, Spain

City Clinical Hospital #3; 🇺🇦 Zaporizhzhya, Ukraine

Chaim Sheba Medical Center; 🇮🇱 Ramat Gan, Israel

Sieff Medical Center; 🇮🇱 Safed, Israel

Worthwhile Clinical Trials, Lakeview Hospital; 🇿🇦 Benoni, South Africa

University Hospital de Elche, Infectious Diseases Unit; 🇪🇸 Elche, Spain

Vinogradov Moscow Municipal Hospital, Department of Surgery #14; 🇷🇺 Moscow, Russian Federation

Public Non-Profit Enterprise: O.O. Shalimov City Clinical Hospital #2 under Kharkiv City Council; 🇺🇦 Kharkiv, Ukraine

Ondokuz Mayis University School of Medicine, Department of Infectious Diseases; 🇹🇷 Samsun, Turkey

L.A. Vorokhobov City Clinical Hospital #67; 🇷🇺 Moscow, Russian Federation

University Hospital Mutua de Terrassa, Unit of Infectious Diseases; 🇪🇸 Terrassa, Spain

V.T. Zaitsev Institute of General and Emergency Surgery; 🇺🇦 Kharkiv, Ukraine

"LAIKO" General Hospital, 1st Department of Internal Medicine; 🇬🇷 Athens, Greece

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

Multiprofile Hospital for Active Treatment "Dr. Ivan Seliminski", Sliven, Anesthesiology and Intensive Care Department; 🇧🇬 Sliven, Bulgaria

Fray Antonio Alcalde Guadalajara Civil Hospital; 🇲🇽 Guadalajara, Mexico

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

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

University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov", Sofia, Clinic of Purulent-Septic Surgery; 🇧🇬 Sofia, Bulgaria

LTD Institute of Clinical Cardiology; 🇬🇪 Tbilisi, Georgia

LTD Academician Vakhtang Bochorishvili Clinic; 🇬🇪 Tbilisi, Georgia

Clinical Center Kragujevac, Center for Anesthesia and Reanimation; 🇷🇸 Kragujevac, Serbia

LTD High Technology Medical Center University Clinic; 🇬🇪 Tbilisi, Georgia

LTD Academician G. Chapidze Emergency Cardiology Center; 🇬🇪 Tbilisi, Georgia

LTD Central University Clinic After Academic N. Kipshidze; 🇬🇪 Tbilisi, Georgia

INDICASAT SMO / Santo Tomas Hospital, Investigation Department; 🇵🇦 Panamá, Panama

Bnai Zion Medical Center; 🇮🇱 Haifa, Israel

Zvezdara University Medical Center, Clinic of Internal Diseases, Clinical Department of Nephrology and Metabolic Disorders with Dialysis "Prof. dr Vasilije Jovanovic"; 🇷🇸 Belgrade, Serbia

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

City Hospital #33; 🇷🇺 Nizhny Novgorod, Russian Federation

Federal State Budget Institution "Central Clinical Hospital with Polyclinic" under the Presidential Executive Office of Russian Federation; 🇷🇺 Moscow, Russian Federation

Pyatigorsk City Clinical Hospital; 🇷🇺 Pyatigorsk, Russian Federation

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

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

Medical Institute Platense SA; 🇦🇷 La Plata, Argentina

British Sanatorium SA; 🇦🇷 Rosario, Argentina

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

De La Costa Clinic Ltd.; 🇨🇴 Barranquilla, Colombia

JSC Rustavi Central Hospital; 🇬🇪 Rustavi, Georgia

LTD N 5 Clinikal Hospital; 🇬🇪 Tbilisi, Georgia

University Hospital Regensburg, Department of Infectious Diseases; 🇩🇪 Regensburg, Germany

IRCCS-University Hospital San Martino-IST, Infectious Diseases Division; 🇮🇹 Genoa, Italy

Sourasky Medical Center; 🇮🇱 Tel Aviv, Israel

University of Milan-Bicocca- S.Gerardo Hospital; 🇮🇹 Monza, Italy

Dr. Jose Eleuterio Gonzalez Monterrey University Hospital; 🇲🇽 Monterrey, Mexico

St. Joseph Belgorod Regional Clinical Hospital; 🇷🇺 Belgorod, Russian Federation

Regional Clinical Hospital; 🇷🇺 Yaroslavl, Russian Federation

Communal Nonprofit Enterprise "Vinnytsia Regional Clinical Hospital named after N.I. Pirogov Vinnytsia Regional Council"; 🇺🇦 Vinnytsia, Ukraine