Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia

Infective Endocarditis Clinical Trial

— HDSAB  

Official title:

A Phase 2 Multicenter, Randomized, Double-blinded, Study to Describe the Safety, Efficacy, and Pharmacokinetics of Daptomycin 10 mg/kg/Day and Vancomycin for the Treatment of Methicillin-resistant Staphylococcus Aureus Bacteremia

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00695903
• Other study ID #: 3009-013
• Secondary ID: DAP-HDSAB-07-05
• Status: Terminated
• Phase: Phase 2
• Start date: September 17, 2008
• Est. completion date: October 1, 2010

Study information

• Verified date: December 2018
• Source: Cubist Pharmaceuticals LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 38
• Est. completion date: October 1, 2010
• Est. primary completion date: August 24, 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Bacteremia
• Endocarditis
• Endocarditis, Bacterial
• Infective Endocarditis

Intervention

Drug:
• daptomycin
daptomycin 10 mg/kg IV every 24 hours
• vancomycin
Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 µg/mL

Locations

Country	Name	City	State
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	East Carolina University	Greenville	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Cubist Pharmaceuticals LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
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.	On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
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.	End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively)
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.	Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8)