Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia

Staphylococcus Aureus Bacteremia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03138733
• Other study ID #: BPR-CS-009
• Status: Completed
• Phase: Phase 3
• Start date: August 26, 2018
• Est. completion date: March 11, 2022

Study information

• Verified date: October 2023
• Source: Basilea Pharmaceutica
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 390
• Est. completion date: March 11, 2022
• Est. primary completion date: March 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bacteremia
• Staphylococcal Infections
• Staphylococcus Aureus Bacteremia

Intervention

Drug:
• Ceftobiprole medocaril
Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) as a 2 h infusion
• Daptomycin
Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam

Locations

Country	Name	City	State
Argentina	Central Hospital de San Isidro Melchor Posse	Buenos Aires
Argentina	Medical Institute Platense SA	La Plata
Argentina	British Sanatorium SA	Rosario
Bulgaria	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	Multiprofile Hospital for Active Treatment "Dr. Ivan Seliminski", Sliven, Anesthesiology and Intensive Care Department	Sliven
Bulgaria	University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov", Sofia, Clinic of Purulent-Septic Surgery	Sofia
Colombia	De La Costa Clinic Ltd.	Barranquilla
Georgia	JSC Rustavi Central Hospital	Rustavi
Georgia	LTD Academician G. Chapidze Emergency Cardiology Center	Tbilisi
Georgia	LTD Academician Vakhtang Bochorishvili Clinic	Tbilisi
Georgia	LTD Central University Clinic After Academic N. Kipshidze	Tbilisi
Georgia	LTD High Technology Medical Center University Clinic	Tbilisi
Georgia	LTD Institute of Clinical Cardiology	Tbilisi
Georgia	LTD N 5 Clinikal Hospital	Tbilisi
Germany	University Hospital Regensburg, Department of Infectious Diseases	Regensburg
Greece	"LAIKO" General Hospital, 1st Department of Internal Medicine	Athens
Israel	Bnai Zion Medical Center	Haifa
Israel	The Baruch Padeh Medical Center	Poriyya 'Illit
Israel	Chaim Sheba Medical Center	Ramat Gan
Israel	Sieff Medical Center	Safed
Israel	Sourasky Medical Center	Tel Aviv
Italy	IRCCS-University Hospital San Martino-IST, Infectious Diseases Division	Genoa
Italy	University of Milan-Bicocca- S.Gerardo Hospital	Monza
Italy	Giuliano Isontina University Health Authority	Trieste
Italy	Central Friuli University Healthcare Company	Udine
Mexico	Fray Antonio Alcalde Guadalajara Civil Hospital	Guadalajara
Mexico	Dr. Jose Eleuterio Gonzalez Monterrey University Hospital	Monterrey
Panama	INDICASAT SMO / Santo Tomas Hospital, Investigation Department	Panamá
Russian Federation	St. Joseph Belgorod Regional Clinical Hospital	Belgorod
Russian Federation	Federal State Budget Institution "Central Clinical Hospital with Polyclinic" under the Presidential Executive Office of Russian Federation	Moscow
Russian Federation	L.A. Vorokhobov City Clinical Hospital #67	Moscow
Russian Federation	N.I. Pirogov City Clinical Hospital #1	Moscow
Russian Federation	Vinogradov Moscow Municipal Hospital, Department of Surgery #14	Moscow
Russian Federation	City Hospital #33	Nizhny Novgorod
Russian Federation	Pyatigorsk City Clinical Hospital	Pyatigorsk
Russian Federation	Regional Clinical Hospital	Yaroslavl
Serbia	Zvezdara University Medical Center, Clinic of Internal Diseases, Clinical Department of Nephrology and Metabolic Disorders with Dialysis "Prof. dr Vasilije Jovanovic"	Belgrade
Serbia	Clinical Center Kragujevac, Center for Anesthesia and Reanimation	Kragujevac
South Africa	Worthwhile Clinical Trials, Lakeview Hospital	Benoni
South Africa	Mediclinic Victoria - Practice of R Moodley and MI Sarwan	Tongaat
Spain	Hospital del Mar, Department of Intensive Care	Barcelona
Spain	University Hospital de Elche, Infectious Diseases Unit	Elche
Spain	General University Hospital Gregorio Maranon, Infectious Diseases / Internal Medicine	Madrid
Spain	University Hospital Ramon y Cajal, Department of Infectious Diseases	Madrid
Spain	University Hospital Mutua de Terrassa, Unit of Infectious Diseases	Terrassa
Turkey	Istanbul Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital	Istanbul
Turkey	Ondokuz Mayis University School of Medicine, Department of Infectious Diseases	Samsun
Ukraine	Dnipropetrovsk City Multispecialty Clinical Hospital #4	Dnipro
Ukraine	Dnipropetrovsk I.I. Mechnykov Regional Clinical Hospital	Dnipro
Ukraine	Ivano-Frankivsk Regional Clinical Hospital	Ivano-Frankivs'k
Ukraine	Public Non-Profit Enterprise: O.O. Shalimov City Clinical Hospital #2 under Kharkiv City Council	Kharkiv
Ukraine	V.T. Zaitsev Institute of General and Emergency Surgery	Kharkiv
Ukraine	Communal Nonprofit Enterprise "Vinnytsia Regional Clinical Hospital named after N.I. Pirogov Vinnytsia Regional Council"	Vinnytsia
Ukraine	City Clinical Hospital #3	Zaporizhzhya
United States	Mercury Street Medical Group	Butte	Montana
United States	eStudy Site - Chula Vista - PPDS	Chula Vista	California
United States	Remington Davis Inc.	Columbus	Ohio
United States	eStudy Site - Las Vegas - PPDS	Las Vegas	Nevada
United States	Triple O Medical Services Inc	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Basilea Pharmaceutica	Department of Health and Human Services

Countries where clinical trial is conducted

United States,  Argentina,  Bulgaria,  Colombia,  Georgia,  Germany,  Greece,  Israel,  Italy,  Mexico,  Panama,  Russian Federation,  Serbia,  South Africa,  Spain,  Turkey,  Ukraine, 

References & Publications (2)

Hamed K, Engelhardt M, Jones ME, Saulay M, Holland TL, Seifert H, Fowler VG Jr. Ceftobiprole versus daptomycin in Staphylococcus aureus bacteremia: a novel protocol for a double-blind, Phase III trial. Future Microbiol. 2020 Jan;15(1):35-48. doi: 10.2217/fmb-2019-0332. Epub 2020 Jan 10. — View Citation

Holland TL, Cosgrove SE, Doernberg SB, Jenkins TC, Turner NA, Boucher HW, Pavlov O, Titov I, Kosulnykov S, Atanasov B, Poromanski I, Makhviladze M, Anderzhanova A, Stryjewski ME, Assadi Gehr M, Engelhardt M, Hamed K, Ionescu D, Jones M, Saulay M, Smart J, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)