Endocarditis, Bacterial, Infective Endocarditis
Conditions
Keywords
Gram-positive bacterial infections, Staph Aureus, Bacteremia, MRSA, Infective Endocarditis, Right-sided Infective endocarditis, SABIE, SAIE, RIE
Brief summary
The overall goals of this study are to compare the safety and efficacy of daptomycin monotherapy 10 mg/kg/day and vancomycin monotherapy dosed to achieve vancomycin trough levels of 15 to 20 μg/mL for the treatment of methicillin-resistant S. aureus bacteremia (MRSA), including right-sided infective endocarditis (RIE).
Detailed description
Patients who meet all inclusion criteria and exhibit none of the exclusion criterial will be randomized to one of two treatment arms: 1. daptomycin Intravenously (IV) 10 mg/kg every 24 hours 2. vancomycin IV dosed to maintain trough levels of 15 to 20 μg/mL. The suggested duration of therapy with daptomycin or vancomycin will be 28 days (or up to 42 days if clinically indicated). Dose adjustments for both drugs will be made by an unblinded pharmacist at each site. To minimize the duration with which patients are treated with antibacterial agents effective against S. aureus prior to enrollment, patients with suspected MRSA bacteremia will be enrolled pending definitive culture results. Suspected MRSA bacteremia will be defined clinically or as initial blood cultures that grow Gram-positive cocci and that were obtained from a patient at increased risk for methicillin-resistant S. aureus infections. However, only patients with confirmed MRSA bacteremia or right-sided infective endocarditis will remain in the study and be evaluated for efficacy. During treatment, regular assessments will be performed. An End-of Therapy (EOT) will be performed 1-3 days after stopping therapy or upon Early Termination (ET). All patients will have a post therapy visit for Test of Cure (TOC) performed 35-49 days following last dose of study drug.
Interventions
DRUGdaptomycin
daptomycin 10 mg/kg IV every 24 hours
DRUGvancomycin
Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent has been obtained; * ≥18 years of age; * Suspected MRSA bacteremia determined by clinical judgment or 2 sets of positive blood cultures; * Increased risk for an MRSA infection
Exclusion criteria
* Received \>48 hours of vancomycin therapy in the 7 days prior to enrollment; * Received any systemic antibacterial agents potentially effective against MRSA in the 7 days prior to enrollment; * Anticipated requirement of antibiotics potentially effective against MRSA; * High likelihood of left-sided infective endocarditis (LIE); * Known/suspected polymicrobial bacteremia or infection including Gram-negative infections; * Known pneumonia, osteomyelitis, or meningitis; * Intravascular foreign material unless material intended removed within 3 days; * Prosthetic heart valve; * Cardiac decompensation, valve damage, or both such that high likelihood of valve replacement surgery within first 3 days of study drug treatment; * Moribund clinical condition such that death likely within first 3 days of study drug treatment; * Shock or hypotension or oliguria unresponsive to fluids after 4 hours; * Received investigational drug within 30 days of study entry * Received statins or other therapy with associated with rhabdomyolysis within 2 days of study entry; * History of significant allergy or intolerance to vancomycin or daptomycin * Infecting pathogen with confirmed reduced susceptibility to vancomycin; * Infecting pathogen with confirmed reduced susceptibility to daptomycin * Creatinine clearance \<30 mL/min (Cockcroft-Gault equation actual body weight) * Serum creatine phosphokinase (CPK) ≥500 U/L * Alanine transaminase (ALT) or aspartate aminotransferase (AST) \>5 X ULN; * Total bilirubin ≥3.0 mg/dL; * Severe neutropenia or expected development severe neutropenia during study; * Known or suspected HIV infection with a CD4+ T-cell count \<200/μL; * Unlikely to comply with study procedures or return for evaluations; * Body Mass Index (BMI) ≥40 kg/m2; * Pregnant or nursing; * Female of childbearing potential not willing to practice barrier methods of birth control. CONTINUATION CRITERIA: * Fulfills A or B or both: A) Confirmed complicated MRSA bacteremia B) Possible or definite RIE caused by MRSA according to modified Duke criteria; * Infecting S. aureus strain susceptible to vancomycin; * Infecting S. aureus strain susceptible to daptomycin; * Appropriate treatment of any foci of infection within first 3 days of study; * Removal of any intravascular foreign material not allowed per inclusion criteria within first 3 days of study; * Removal of any percutaneous or implanted catheters not allowed per inclusion criteria within first 3 days of study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations | On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days) | Number of participants with treatment-emergent CPK elevations ≥5 x upper limit of normal (≥1,000 U/L) by the EOT visit. |
| Number of Participants With Elevated Serum Creatinine | On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days) | Number of participants with treatment-emergent serum creatinine increases ≥0.5 mg/dL (for patients with a baseline value ≤3.0 mg/dL) or ≥1.0 mg/dL (for patients with a baseline value \>3.0 mg/dL) by the EOT visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Cure at End of Therapy (EOT) Visit | End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively) | Investigator's assessment of treatment cure. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy. |
| Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit | Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8) | Investigator's assessment of clinical response. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin 10 mg/kg Daptomycin 10 mg/kg Intravenously (IV) every 24 hours | 19 |
| Vancomycin High-dose Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL | 17 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Had End of Therapy (EOT) Assessment | Adverse Event | 1 | 0 |
| Had End of Therapy (EOT) Assessment | No confirmed MRSA | 9 | 9 |
| Had End of Therapy (EOT) Assessment | Physician Decision | 0 | 1 |
| Had End of Therapy (EOT) Assessment | Protocol Violation | 1 | 2 |
| Had End of Therapy (EOT) Assessment | Randomized not treated | 0 | 2 |
| Had End of Therapy (EOT) Assessment | Withdrawal by Subject | 1 | 1 |
| Had Test of Cure (TOC) Assessment | Adverse Event | 0 | 1 |
| Had Test of Cure (TOC) Assessment | Lack of Efficacy | 1 | 0 |
| Had Test of Cure (TOC) Assessment | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Daptomycin 10 mg/kg | Vancomycin High-dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 15 Participants | 31 Participants |
| Sex: Female, Male Female | 6 Participants | 4 Participants | 10 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 19 | 10 / 17 |
| serious Total, serious adverse events | 3 / 19 | 4 / 17 |
Outcome results
Primary
Number of Participants With Elevated Serum Creatinine
Number of participants with treatment-emergent serum creatinine increases ≥0.5 mg/dL (for patients with a baseline value ≤3.0 mg/dL) or ≥1.0 mg/dL (for patients with a baseline value \>3.0 mg/dL) by the EOT visit.
Time frame: On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
Population: All subjects who received at least one dose of study medication (Safety Population). Two patients in the high-dose vancomycin arm were randomized but not treated and therefore not included in the safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin 10 mg/kg | Number of Participants With Elevated Serum Creatinine | 0 participants |
| Vancomycin High-dose | Number of Participants With Elevated Serum Creatinine | 4 participants |
Primary
Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations
Number of participants with treatment-emergent CPK elevations ≥5 x upper limit of normal (≥1,000 U/L) by the EOT visit.
Time frame: On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
Population: All subjects who received at least one dose of study medication (Safety Population). Two patients in the high-dose vancomycin arm were randomized but not treated and therefore not included in the safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin 10 mg/kg | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations | 2 Participants |
| Vancomycin High-dose | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations | 0 Participants |
Secondary
Number of Participants With Treatment Cure at End of Therapy (EOT) Visit
Investigator's assessment of treatment cure. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.
Time frame: End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively)
Population: Patients who met the continuation criteria (modified intent-to-treat) and had a EOT assessment of clinical outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin 10 mg/kg | Number of Participants With Treatment Cure at End of Therapy (EOT) Visit | 6 participants |
| Vancomycin High-dose | Number of Participants With Treatment Cure at End of Therapy (EOT) Visit | 3 participants |
Secondary
Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit
Investigator's assessment of clinical response. Treatment Cure includes successful outcomes of both clinical and microbiological assessments. Clinical cure is defined by clinical improvement of symptoms and signs associated with the underlying infection such that no further anti-infective therapy is required. Microbiological Success is defined by the eradication or presumed eradication of baseline infecting methicillin-resistant S. aureus pathogen and no superinfecting pathogen(s) (Gram-positive) or metastatic methicillin-resistant S. aureus pathogens were isolated post therapy.
Time frame: Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8)
Population: Subset of modified intent-to-treat population who completed TOC/Safety visit
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin 10 mg/kg | Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit | 5 participants |
| Vancomycin High-dose | Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit | 3 participants |