Staphylococcus Aureus Bacteremia, Staphylococcus Aureus Endocarditis
Conditions
Keywords
S. aureus bloodstream infection, S. aureus bacteremia, S. aureus right-sided infective endocarditis
Brief summary
The purpose of this superiority study is to evaluate the efficacy and safety of exebacase in addition to standard of care antibiotics (SoCA) compared with SoCA alone for the treatment of patients with Staphylococcus aureus (S. aureus) bloodstream infections (BSI), including right-sided infective endocarditis (IE). Patients will be randomized to receive a single intravenous dose of exebacase or placebo. Patients will receive SoCA selected by the investigators based on the protocol. Exebacase, a direct lytic agent, is an entirely new treatment modality against S. aureus. Exebacase is a recombinantly-produced, purified cell wall hydrolase enzyme that results in rapid bacteriolysis, potent biofilm eradication, synergy with antibiotics, low propensity for resistance, and the potential to suppress antibiotic resistance when used together with antibiotics. Exebacase represents a first-in-field, first-in-class treatment with the potential to improve clinical outcome when used in addition to SoCA to treat S. aureus BSI including IE.
Interventions
DRUGExebacase
Participants will receive a single IV infusion of exebacase in addition to SoCA selected by the investigator. Participants with normal renal function or mild renal impairment will be administered a dose of 18 mg; participants with moderate or severe renal impairment will be administered a dose of 12 mg of exebacase; participants with end-stage renal disease, including those on hemodialysis, will be administered a dose of 8 mg of exebacase.
DRUGPlacebo
Participants will receive a single IV infusion of placebo in addition to SoCA selected by the investigator.
Sponsors
ContraFect
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, 12 years or older * Blood culture positive for S. aureus * At least two signs or symptoms attributable to S. aureus BSI/IE * Known or suspected complicated S. aureus BSI and/or right-sided IE based on Modified Duke Criteria * Not pregnant or breastfeeding and not of reproductive potential or agrees to remain abstinent or use contraception if of reproductive potential
Exclusion criteria
* Previously received exebacase * Known or suspected left-sided IE * Treatment with effective systemic anti-staphylococcal antibiotic for more than 72 hours within 7 days before randomization * Presence of prosthetic valve or cardiac valve support ring, or presence of known or suspected infected hardware (orthopedic), prosthetic joint, or cardiac device * Known polymicrobial BSI, or known ongoing systemic infection caused by other bacterial and/or fungal pathogen(s), and/or known to have coronavirus disease 2019 (COVID-19)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Day 14 | Clinical outcome of responder was defined as survival with resolution or 2-grade improvement of attributable signs and symptoms and negative blood cultures by Day 14, and without new signs or symptoms, new metastatic foci or septic emboli, or change in antibiotics due to lack of response. |
| Treatment-emergent Adverse Events (TEAEs) Through Day 60 | Through Day 60 | Number and percentage of patients with treatment-emergent adverse events (TEAEs) |
Countries
United States
Participant flow
Recruitment details
Approximately 348 patients were planned, and 259 patients were randomized at the time the study was stopped for futility.
Participants by arm
| Arm | Count |
|---|---|
| Exebacase + SoCA Participants received a single IV infusion of exebacase in addition to standard-of-care antibiotics (SoCA) selected by the investigator. | 165 |
| SoCA Alone Participants received a single IV infusion of placebo in addition to standard-of-care antibiotics (SoCA) selected by the investigator. | 85 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 19 | 4 |
| Overall Study | Participant incarcerated | 1 | 0 |
| Overall Study | Participant unable/unwilling to adhere to protocol | 1 | 0 |
| Overall Study | Randomized but not dosed | 6 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Exebacase + SoCA | SoCA Alone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical >=65 years | 44 Participants | 22 Participants | 66 Participants |
| Age, Categorical Between 18 and 65 years | 119 Participants | 63 Participants | 182 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 10 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 138 Participants | 75 Participants | 213 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants | 0 Participants | 7 Participants |
| Final Adjudicated Diagnosis Complicated bloodstream infection | 127 Participants | 63 Participants | 190 Participants |
| Final Adjudicated Diagnosis Left-sided infective endocarditis | 4 Participants | 3 Participants | 7 Participants |
| Final Adjudicated Diagnosis Right- and left-sided infective endocarditis | 1 Participants | 0 Participants | 1 Participants |
| Final Adjudicated Diagnosis Right-sided infective endocarditis | 22 Participants | 10 Participants | 32 Participants |
| Final Adjudicated Diagnosis Uncomplicated bloodstream infection | 11 Participants | 9 Participants | 20 Participants |
| Methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) MRSA | 64 Participants | 33 Participants | 97 Participants |
| Methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) MSSA | 101 Participants | 52 Participants | 153 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 16 Participants | 44 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) White | 118 Participants | 65 Participants | 183 Participants |
| Region of Enrollment United States | 165 participants | 85 participants | 250 participants |
| Sex: Female, Male Female | 110 Participants | 48 Participants | 158 Participants |
| Sex: Female, Male Male | 55 Participants | 37 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 27 / 165 | 14 / 85 |
| other Total, other adverse events | 72 / 165 | 41 / 85 |
| serious Total, serious adverse events | 71 / 165 | 34 / 85 |
Outcome results
Primary
Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set
Clinical outcome of responder was defined as survival with resolution or 2-grade improvement of attributable signs and symptoms and negative blood cultures by Day 14, and without new signs or symptoms, new metastatic foci or septic emboli, or change in antibiotics due to lack of response.
Time frame: Day 14
Population: MRSA population in the mITT analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Exebacase + SoCA | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Responder | 32 Participants |
| Exebacase + SoCA | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Failure | 30 Participants |
| Exebacase + SoCA | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Indeterminate | 2 Participants |
| SoCA Alone | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Responder | 20 Participants |
| SoCA Alone | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Failure | 13 Participants |
| SoCA Alone | Clinical Responder Rate at Day 14 in the MRSA Population in the Microbiological Intent-to-treat (mITT) Analysis Set | Indeterminate | 0 Participants |
p-value: 0.39295% CI: [-33.6, 12.4]Fisher Exact
Primary
Treatment-emergent Adverse Events (TEAEs) Through Day 60
Number and percentage of patients with treatment-emergent adverse events (TEAEs)
Time frame: Through Day 60
Population: Safety analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Exebacase + SoCA | Treatment-emergent Adverse Events (TEAEs) Through Day 60 | 142 Participants |
| SoCA Alone | Treatment-emergent Adverse Events (TEAEs) Through Day 60 | 72 Participants |