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

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

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).

Study Overview

• Status: Terminated
• Conditions: Infective Endocarditis; Endocarditis, Bacterial
• Intervention / Treatment: Drug: daptomycin; Drug: vancomycin

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Greenville, North Carolina, United States
      • East Carolina University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: daptomycin 10 mg/kg; Daptomycin 10 mg/kg IV every 24 hours	Drug: daptomycin; daptomycin 10 mg/kg IV every 24 hours; Other Names: Cubicin; daptomycin for injection
EXPERIMENTAL: vancomycin high-dose; Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL	Drug: vancomycin; Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL; Other Names: vancocin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)
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)

Collaborators and Investigators

• Sponsor: Cubist Pharmaceuticals LLC
• Investigators: Study Director: Peter Pertel, MD, Cubist Pharmaceuticals LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 17, 2008
• Primary Completion (ACTUAL): August 24, 2010
• Study Completion (ACTUAL): October 1, 2010

Study Registration Dates

• First Submitted: June 10, 2008
• First Submitted That Met QC Criteria: June 10, 2008
• First Posted (ESTIMATE): June 12, 2008

Study Record Updates

• Last Update Posted (ACTUAL): December 24, 2018
• Last Update Submitted That Met QC Criteria: December 3, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: MRSA; Bacteremia; Infective Endocarditis; Gram-positive bacterial infections; Staph Aureus; Right-sided Infective endocarditis; SABIE; SAIE; RIE
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Cardiovascular Infections; Bacteremia; Endocarditis, Bacterial; Endocarditis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin; Daptomycin
• Other Study ID Numbers: 3009-013; DAP-HDSAB-07-05 (OTHER: Cubist Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf