Trial Outcomes & Findings for Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia (NCT NCT03138733)

Last Updated: 2023-11-08

Results Overview

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)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

390 participants

Primary outcome timeframe

PTE visit on Day 70 (± 5 days) post-randomization

Results posted on

2023-11-08

Participant Flow

Hospitalized male or female patients aged ≥ 18 years who had complicated Staphylococcus aureus bacteremia (SAB). SAB, based on ≥ 1 positive blood culture obtained within 72 h prior to randomization, with signs or symptoms of bloodstream infection

A total of 390 patients were randomized and comprised the Intent-to-Treat (ITT) population (ceftobiprole n = 192; comparator n = 198). Three of these patients were excluded from the modified ITT (mITT) population: one patient in the ceftobiprole group who discontinued prior to receiving study treatment, and two patients in the ceftobiprole group who were determined by central laboratory results not to have a confirmed positive blood culture for Staphylococcus aureus at baseline

Participant milestones

Participant milestones
Measure	Ceftobiprole Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Overall Study STARTED	192	198
Overall Study Modified ITT (mITT)	189	198
Overall Study COMPLETED	157	169
Overall Study NOT COMPLETED	35	29

Reasons for withdrawal

Reasons for withdrawal
Measure	Ceftobiprole Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Overall Study Death	17	18
Overall Study Withdrawal by Subject	11	6
Overall Study Lost to Follow-up	3	2
Overall Study Adverse Event	1	0
Overall Study Protocol Violation	1	3
Overall Study Administrative or logistical reason	1	0
Overall Study The patient was transferred to another hospital	1	0

Baseline Characteristics

Ceftobiprole in the Treatment of Patients With Staphylococcus Aureus Bacteremia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam	Total n=387 Participants Total of all reporting groups
Age, Continuous	55.5 years STANDARD_DEVIATION 15.18 • n=5 Participants	56.5 years STANDARD_DEVIATION 15.33 • n=7 Participants	56.0 years STANDARD_DEVIATION 15.25 • n=5 Participants
Sex: Female, Male Female	128 Participants n=5 Participants	140 Participants n=7 Participants	268 Participants n=5 Participants
Sex: Female, Male Male	61 Participants n=5 Participants	58 Participants n=7 Participants	119 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	14 Participants n=5 Participants	15 Participants n=7 Participants	29 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	174 Participants n=5 Participants	182 Participants n=7 Participants	356 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Black or African American	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	179 Participants n=5 Participants	192 Participants n=7 Participants	371 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment Europe	175 Participants n=5 Participants	185 Participants n=7 Participants	360 Participants n=5 Participants
Region of Enrollment North America	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment Central America	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Region of Enrollment South America	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Region of Enrollment South Africa	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Aztreonam treatment at baseline	0 Participants n=5 Participants	62 Participants n=7 Participants	62 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Skin and skin structure infection	116 Participants n=5 Participants	121 Participants n=7 Participants	237 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Intra-abdominal abscess	26 Participants n=5 Participants	29 Participants n=7 Participants	55 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Chronic dialysis	24 Participants n=5 Participants	25 Participants n=7 Participants	49 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Septic arthritis	22 Participants n=5 Participants	19 Participants n=7 Participants	41 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Persistent SAB	16 Participants n=5 Participants	16 Participants n=7 Participants	32 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Osteomyelitis	13 Participants n=5 Participants	17 Participants n=7 Participants	30 Participants n=5 Participants
Most frequent baseline categories of complicated SAB (Investigator-assessed) Definite right-sided endocarditis	15 Participants n=5 Participants	10 Participants n=7 Participants	25 Participants n=5 Participants

PRIMARY outcome

Timeframe: PTE visit on Day 70 (± 5 days) post-randomization

Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline

Outcome measures

Outcome measures
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit Number of responders	132 Participants	136 Participants
Number of Patients With or Without Overall Success at the Post-treatment Evaluation (PTE) Visit Number of non-responders	57 Participants	62 Participants

SECONDARY outcome

Timeframe: At PTE visit on Day 70 (± 5 days) post-randomization

Population: The CE population comprised the subset of patients in the mITT population who complied with important pre-specified aspects of the study

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)

Outcome measures

Outcome measures
Measure	Ceftobiprole n=163 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=167 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Number of Patients With or Without Overall Success at the PTE Visit in the CE Population Number of responders	127 Participants	130 Participants
Number of Patients With or Without Overall Success at the PTE Visit in the CE Population Number of non-responders	36 Participants	37 Participants

SECONDARY outcome

Timeframe: At PTE visit on Day 70 (± 5 days) post-randomization

Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline

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.

Outcome measures

Outcome measures
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Number of Patients With Microbiological Eradication at the PTE Visit	155 Participants	153 Participants

SECONDARY outcome

Timeframe: At PTE visit on Day 70 (± 5 days) post-randomization

Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline

Comparison of all-cause mortality rates in the mITT population

Outcome measures

Outcome measures
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
All-cause Mortality at the PTE Visit Patients alive	172 Participants	180 Participants
All-cause Mortality at the PTE Visit Patients died	17 Participants	18 Participants

SECONDARY outcome

Timeframe: Assessment after Day 7 post-randomization through to post-treatment evaluation (PTE) visit on Day 70 (± 5 days)

Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline

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

Outcome measures

Outcome measures
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 Patients with development of new metastatic foci or other complications of SAB after Day 7	11 Participants	11 Participants
Number of Patients With or Without New Metastatic Foci or Other Complications of SAB Developed After Day 7 Patients without development of new metastatic foci or other complications of SAB after Day 7	178 Participants	187 Participants

SECONDARY outcome

Timeframe: Up to 6 weeks post-randomization

Population: The mITT population comprised the subset of patients in the ITT population who received any dose of study medication, and had a blood culture positive for S. aureus at baseline

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

Outcome measures

Outcome measures
Measure	Ceftobiprole n=189 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Time to Staphylococcus Aureus Bloodstream Clearance	4 Days Interval 3.0 to 5.0	4 Days Interval 3.0 to 5.0

SECONDARY outcome

Timeframe: AEs were assessed from the first dose of study drug through the post-treatment evaluation (PTE) visit on Day 70 (± 5 days)

Population: The Safety population comprised all randomized patients who received any dose of study drug. Patients in the Safety population were analyzed according to the first study drug received.

Treatment-emergent adverse events in the safety population

Outcome measures

Outcome measures
Measure	Ceftobiprole n=191 Participants Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 Participants Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Number of Patients With or Without Adverse Events (AEs) Any adverse events (AEs)	121 Participants	117 Participants
Number of Patients With or Without Adverse Events (AEs) Any drug-related AE	25 Participants	11 Participants
Number of Patients With or Without Adverse Events (AEs) Any severe AEs	29 Participants	38 Participants
Number of Patients With or Without Adverse Events (AEs) Any study drug-related severe AEs	1 Participants	2 Participants
Number of Patients With or Without Adverse Events (AEs) Any serious adverse events (SAE)	36 Participants	45 Participants
Number of Patients With or Without Adverse Events (AEs) Any drug-related SAEs	2 Participants	4 Participants
Number of Patients With or Without Adverse Events (AEs) Any AE leading to treatment discontinuation	18 Participants	18 Participants
Number of Patients With or Without Adverse Events (AEs) Study drug-related AEs leading to treatment discontinuation	9 Participants	3 Participants
Number of Patients With or Without Adverse Events (AEs) Any AE leading to death	17 Participants	18 Participants
Number of Patients With or Without Adverse Events (AEs) Study drug-related AEs leading to death	0 Participants	0 Participants
Number of Patients With or Without Adverse Events (AEs) Any AE of special interest (AESI)	9 Participants	7 Participants
Number of Patients With or Without Adverse Events (AEs) Any drug-related AESI	5 Participants	4 Participants

Adverse Events

Ceftobiprole

Serious events: 36 serious events

Other events: 61 other events

Deaths: 17 deaths

Daptomycin

Serious events: 45 serious events

Other events: 45 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Ceftobiprole n=191 participants at risk Ceftobiprole 500 mg (as 667 mg ceftobiprole medocaril) Ceftobiprole: Ceftobiprole 500 mg as a 2 h infusion	Daptomycin n=198 participants at risk Daptomycin 6 mg/kg, with or without aztreonam Daptomycin: Daptomycin 6 mg/kg (up to 10 mg/kg based on institutional standards) as a 0.5 h infusion, with or without aztreonam
Investigations Blood potassium decreased	8.9% 17/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	2.5% 5/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.
Investigations Gamma-glutamyltransferase increased	6.3% 12/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	7.6% 15/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.
Blood and lymphatic system disorders Anaemia	10.5% 20/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	12.1% 24/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.
Gastrointestinal disorders Diarrhoea	6.8% 13/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	2.5% 5/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.
Gastrointestinal disorders Nausea	10.5% 20/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	4.0% 8/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.
Gastrointestinal disorders Vomiting	8.4% 16/191 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.	2.0% 4/198 • All AEs occurring from the start of first dosing up to and including the scheduled PTE visit on Day 70 (± 5 days) were collected. All AEs were defined as treatment-emergent AEs (TEAEs), i.e., occurring from the start of first dosing up to and including the scheduled PTE visit, and were considered for the analysis purpose.

Additional Information

Dr Marc Engelhardt, MD

Basilea Pharmaceutica

Phone: +41 79 701 0551

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60