Phase 4 Efficacy and Safety Study of Cubicin® With and Without Combination Therapy in S. Aureus Infective Endocarditis (SAIE)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 4 Multicenter, Randomized, Double Blind Study to Describe the Efficacy and Safety of Cubicin® (Daptomycin for Injection) With and Without Initial Gentamicin Combination Therapy in the Treatment of S. Aureus Infective Endocarditis

Conditions
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Infective Endocarditis

Intervention / Treatment
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* Drug: daptomycin
* Drug: daptomycin and gentamicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent has been obtained; Male or female ≥18 years of age; IVDU (as confirmed by history of drug abuse within the past 3 months or recent needle track marks); Definite or possible IE according to the modified Duke Criteria (see Appendix A); [17 ]; 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: 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); High likelihood of LIE as indicated by: Prior diagnosis of predisposing left-sided valvular pathology (e.g., rheumatic heart disease, bicuspid aortic valve); or Findings on screening examination of left-sided valvular pathology (e.g., diastolic murmur of aortic insufficiency); or 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. Prosthetic heart valve; Baseline Creatinine clearance of <30 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight); 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; Alanine aminotransferase (ALT) >5 X ULN; Aspartate aminotransferase (AST) >5 X ULN; Moribund clinical condition (i.e. high likelihood of death within 3 days after randomization); 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; Known pneumonia or osteomyelitis; Polymicrobial infection or bacteremia due to a pathogen other than S. aureus; Neutropenia (absolute neutrophil count < 0.5 X 103/μL) and/or lymphopenia (CD4 lymphocytes <0.2X 103/μL); Anticipated to require non-study antibiotics that may be potentially effective against S. aureus; Prior gentamicin therapy > 1 day; Documented history of significant allergy or intolerance to any of the study medications; Unlikely to comply with study procedures; Pregnant or nursing. All females with childbearing potential will have a pregnancy test performed at the local laboratory. 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Daptomycin Alone<br>daptomycin 6 mg/kg q24h for treatment of right-sided infective endocarditis | Drug: daptomycin<br>* Intravenous (i.v.) 6 mg/kg q24h<br>* Other names: daptomycin for injection;|
| Experimental: Daptomycin plus gentamicin<br>daptomycin 6 mg/kg q24h with concomitant initial gentamicin dosed for the first 2 days of therapy for the treatment of right-sided infective endocarditis | Drug: daptomycin and gentamicin<br>* i.v. daptomycin 6 mg/kg q24h plus initial i.v. gentamicin<br>* Other names: gentamicin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, EOT Visit, TOC | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | TOC Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gram-positive bacterial infections, Staph Aureus, endocarditis, bacteremia, methicillin-resistant Staphylococcus aureus (MRSA)