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

Study Description

Brief Summary

Detailed Description

Condition or disease	Intervention/treatment	Phase
Infective Endocarditis	Drug: daptomycin Other Names Cubicin daptomycin for injection Drug: daptomycin and gentamicin Other Names Cubicin daptomycin for injection gentamicin	Phase 4

Tracking Information

First Submitted Date	March 12, 2008
Last Update Posted Date	January 05, 2016
Start Date	March 01, 2008
Actual Completion Date	November 01, 2011
Primary Completion Date	November 01, 2011
Results First Submitted Date	March 04, 2013
Received Results Disposit Date	N/A

Current Primary Outcome Measures

• Summary of Clinically Significant Increases in Serum Creatinine by Visit [Time Frame: 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.

Original Primary Outcome Measures

• 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.

Current Secondary Outcome Measures

• Summary of the Investigator's Assessment of Clinical Response at the TOC Visit [Time Frame: 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.

Original Secondary Outcome Measures

• 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.

Study Design

Brief Title	Phase 4 Efficacy and Safety Study of Cubicin® With and Without Combination Therapy in S. Aureus Infective Endocarditis (SAIE)
Official Title	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
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.
Study Type	Interventional
Study Phase	Phase 4
Estimated Enrollment	24
Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	Double
Primary Purpose	Treatment
Conditions	Infective Endocarditis
Target Follow-Up Duration	N/A
Biospecimen:	N/A
Sampling Method	N/A
Study Population	N/A
Intervention	Drug: daptomycin Intravenous (i.v.) 6 mg/kg q24h Other Names Cubicin daptomycin for injection Drug: daptomycin and gentamicin i.v. daptomycin 6 mg/kg q24h plus initial i.v. gentamicin Other Names Cubicin daptomycin for injection gentamicin
Study Groups/Cohorts	Daptomycin Alone daptomycin 6 mg/kg q24h for treatment of right-sided infective endocarditis Daptomycin plus gentamicin 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
Study Arms	Active Comparator Daptomycin Alone daptomycin 6 mg/kg q24h for treatment of right-sided infective endocarditis Drug : daptomycin Intravenous (i.v.) 6 mg/kg q24h Experimental Daptomycin plus gentamicin 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 i.v. daptomycin 6 mg/kg q24h plus initial i.v. gentamicin

Arm	Intervention/Treatment
Active Comparator Daptomycin Alone daptomycin 6 mg/kg q24h for treatment of right-sided infective endocarditis	Drug : daptomycin Intravenous (i.v.) 6 mg/kg q24h
Experimental Daptomycin plus gentamicin 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 i.v. daptomycin 6 mg/kg q24h plus initial i.v. gentamicin

Recruitment Information

Recruitment Status:	Terminated
Enrollment	24
Completion Date	November 01, 2011
Eligibility Criteria:	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
Gender	All
Age	18 Years to N/A
Accepts Healthy Volunteers	No
Contacts	Not Available
Listed Location Countries	United States

Administrative Information

NCT Number:	NCT00638157
Other Study ID Numbers	3009-010 DAP-4IE-06-03
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement	Not Available
Responsible Party	,
Study Sponsor	Cubist Pharmaceuticals LLC
Collaborators	Not Available
Investigators	Study Director Paula Bokesch, M.D. Cubist Pharmaceuticals LLC