Infective Endocarditis
Conditions
Keywords
Gram-positive bacterial infections, Staph Aureus, endocarditis, bacteremia, methicillin-resistant Staphylococcus aureus (MRSA)
Brief summary
multicenter, randomized, double blind study to describe the safety and efficacy of daptomycin (6 mg/kg q24h) with and without concomitant initial gentamicin combination therapy in the treatment of SAIE
Detailed description
Patients will be randomized to either of the following two treatment arms: * Arm 1: daptomycin * Arm 2: daptomycin with initial i.v. gentamicin Patients who meet all the inclusion criteria and exhibit none of the exclusion criteria may be enrolled. Intravenous drug user (IVDU) patients may be randomized and study drug begun on the basis of two separate peripheral blood cultures positive for S. aureus obtained within 96 hours prior to the first dose of study drug. The recommended minimum duration of treatment for daptomycin will be 28 days. The duration of treatment for gentamicin will be 3 days. During study treatment, regular assessments (including weekly safety laboratory testing including CPK) will be performed. An End-of-Therapy (EOT) evaluation will be performed on the day of or 1-2 days after completion of daptomycin study drug or upon early termination (ET). All patients will have a post-therapy visit for Test of Cure (TOC)/Safety performed 21-28 days following the last dose of daptomycin study drug.
Interventions
DRUGdaptomycin
Intravenous (i.v.) 6 mg/kg q24h
DRUGdaptomycin and gentamicin
i.v. daptomycin 6 mg/kg q24h plus initial i.v. gentamicin
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
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent has been obtained; 2. Male or female ≥18 years of age; 3. IVDU (as confirmed by history of drug abuse within the past 3 months or recent needle track marks); 4. Definite or possible IE according to the modified Duke Criteria (see Appendix A); \[17 \]; 5. Two blood cultures positive for S. aureus obtained within 96 hours prior to first dose of study medication acquired by fresh venipuncture using aseptic technique and analyzed at the local laboratory (see Appendix B).
Exclusion criteria
1. Intravascular foreign material in place at the time that the positive blood culture was drawn (e.g., intracardiac pacemaker wires, percutaneous or implanted venous catheters, vascular grafts), (exception: vascular stents that have been in place for \>6 months or permanent pacemaker wires attached via epicardial leads are allowed); 2. High likelihood of LIE as indicated by: 1. Prior diagnosis of predisposing left-sided valvular pathology (e.g., rheumatic heart disease, bicuspid aortic valve); or 2. Findings on screening examination of left-sided valvular pathology (e.g., diastolic murmur of aortic insufficiency); or 3. Findings on screening examination of major systemic emboli to visceral organs (e.g. cerebral or splenic infarct). Patients may be included if their only findings are consistent with microvascular phenomena due to immune complexes (e.g., splinter hemorrhages, conjunctival petechiae, Roth's spots, Osler's nodes, Janeway's lesions, microhematuria). Note: Any patient enrolled in the study that is subsequently found to have LIE may be continued in the trial if determined to be clinically improving by the Investigator. 3. Prosthetic heart valve; 4. Baseline Creatinine clearance of \<30 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight); 5. Baseline CPK value 5 X upper limit of normal (ULN) in conjunction with symptoms of myalgia or baseline CPK value 10 X ULN without symptoms; 6. Alanine aminotransferase (ALT) \>5 X ULN; 7. Aspartate aminotransferase (AST) \>5 X ULN; 8. Moribund clinical condition (i.e. high likelihood of death within 3 days after randomization); 9. Shock or hypotension (supine systolic blood pressure \<80 mm Hg) or oliguria (urine output \<20 mL/h) unresponsive to fluids or pressors within 4 hours; 10. Known pneumonia or osteomyelitis; 11. Polymicrobial infection or bacteremia due to a pathogen other than S. aureus; 12. Neutropenia (absolute neutrophil count \< 0.5 X 103/μL) and/or lymphopenia (CD4 lymphocytes \<0.2X 103/μL); 13. Anticipated to require non-study antibiotics that may be potentially effective against S. aureus; 14. Prior gentamicin therapy \> 1 day; 15. Documented history of significant allergy or intolerance to any of the study medications; 16. Unlikely to comply with study procedures; 17. Pregnant or nursing. All females with childbearing potential will have a pregnancy test performed at the local laboratory. 18. Female of childbearing potential and not willing to practice barrier methods of birth control (e.g., condoms or diaphragms together with spermicidal foam or gel) during treatment and for at least 28 days after treatment with study medication
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Clinically Significant Increases in Serum Creatinine by Visit | Baseline, EOT Visit, TOC | The End of Treatment (EOT)/Early Termination (ET) visit occurred on the day that therapy was stopped or up to 2 days after the last dose of daptomycin. The Test of Cure (TOC)/Safety visit occurred 21 to 28 days after the last dose of daptomycin therapy. The overall median duration of treatment was 13.0 days in both the daptomycin group and the combination therapy group. The definition of elevated serum creatinine at baseline is \>3.0 mg/dL, and not elevated is ≤3.0 mg/dL. Clinically significant increases in serum creatinine is defined as an increase ≥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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TOC Visit | TOC/Safety visit occurred 21 to 28 days after the last dose of daptomycin therapy. Clinical response was assessed by the investigator as cure, improvement, failure, and unable to evaluate. Microbiological response, which was determined by the sponsor based on review of baseline and post-baseline culture results, included success, failure, and nonevaluable. TC=Treatment Cure; TF=Treatment Failure; TI=Treatment Improved. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin Intravenous daptomycin 6mg/kg every 24 hours for a recommended minimum duration of 28 days plus a dummy infusion of 0.9% normal saline every 8 hours for the first 3 days of daptomycin therapy. | 12 |
| Daptomycin Plus Gentamicin Intravenous daptomycin 6mg/kg every 24 hours for a recommended minimum duration of 28 days plus intravenous gentamicin 1mg/kg every 8 hours for the first 3 days of daptomycin therapy. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Clinical (symptomatic) failure | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Microbiological failure | 1 | 0 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Randomized, not treated | 2 | 0 |
Baseline characteristics
| Characteristic | Daptomycin | Daptomycin Plus Gentamicin | Total |
|---|---|---|---|
| Age, Continuous | 38.9 years STANDARD_DEVIATION 10.93 | 45.3 years STANDARD_DEVIATION 9.9 | 42.1 years STANDARD_DEVIATION 10.71 |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 10 | 11 / 12 |
| serious Total, serious adverse events | 2 / 10 | 5 / 12 |
Outcome results
Primary
Summary of Clinically Significant Increases in Serum Creatinine by Visit
The End of Treatment (EOT)/Early Termination (ET) visit occurred on the day that therapy was stopped or up to 2 days after the last dose of daptomycin. The Test of Cure (TOC)/Safety visit occurred 21 to 28 days after the last dose of daptomycin therapy. The overall median duration of treatment was 13.0 days in both the daptomycin group and the combination therapy group. The definition of elevated serum creatinine at baseline is \>3.0 mg/dL, and not elevated is ≤3.0 mg/dL. Clinically significant increases in serum creatinine is defined as an increase ≥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.
Time frame: Baseline, EOT Visit, TOC
Population: Safety Population includes all patients who received any dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Baseline - No Elevation | 10 Participants |
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Baseline - Any Elevation | 0 Participants |
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | End of Therapy - Any Elevation | 0 Participants |
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | End of Therapy - No Elevation | 10 Participants |
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Test of Cure - Any Elevation (n=8,9) | 0 Participants |
| Daptomycin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Test of Cure - No Elevation (n=8,9) | 8 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Test of Cure - Any Elevation (n=8,9) | 2 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | End of Therapy - No Elevation | 10 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Baseline - Any Elevation | 0 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Baseline - No Elevation | 12 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | Test of Cure - No Elevation (n=8,9) | 7 Participants |
| Daptomycin Plus Gentamicin | Summary of Clinically Significant Increases in Serum Creatinine by Visit | End of Therapy - Any Elevation | 2 Participants |
Secondary
Summary of the Investigator's Assessment of Clinical Response at the TOC Visit
TOC/Safety visit occurred 21 to 28 days after the last dose of daptomycin therapy. Clinical response was assessed by the investigator as cure, improvement, failure, and unable to evaluate. Microbiological response, which was determined by the sponsor based on review of baseline and post-baseline culture results, included success, failure, and nonevaluable. TC=Treatment Cure; TF=Treatment Failure; TI=Treatment Improved.
Time frame: TOC Visit
Population: Modified Intent-to-Treat (mITT) population includes all ITT patients who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological success) | 1 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical improved, microbiological failure) | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological nonevaluable | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical cure, microbiological failure) | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TI (clinical improved, microbiological success) | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TC (clinical cure, microbiological nonevaluable) | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TI (clin improved, microbiological nonevaluable) | 0 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological failure) | 2 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | Non-evaluable | 2 Participants |
| Daptomycin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TC (clinical cure, microbiological success) | 4 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | Non-evaluable | 2 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological success) | 1 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical improved, microbiological failure) | 0 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TC (clinical cure, microbiological success) | 5 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TC (clinical cure, microbiological nonevaluable) | 0 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical cure, microbiological failure) | 0 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological failure) | 0 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TF (clinical failure, microbiological nonevaluable | 2 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TI (clinical improved, microbiological success) | 1 Participants |
| Daptomycin Plus Gentamicin | Summary of the Investigator's Assessment of Clinical Response at the TOC Visit | TI (clin improved, microbiological nonevaluable) | 0 Participants |