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

Primary Purpose

Endocarditis, Bacterial, Infective Endocarditis

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
daptomycin
vancomycin
Sponsored by
Cubist Pharmaceuticals LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Endocarditis, Bacterial focused on measuring Gram-positive bacterial infections, Staph Aureus, Bacteremia, MRSA, Infective Endocarditis, Right-sided Infective endocarditis, SABIE, SAIE, RIE

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • East Carolina University
  • Cleveland Clinic Foundation

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

daptomycin 10 mg/kg

vancomycin high-dose

Arm Description

Daptomycin 10 mg/kg IV every 24 hours

Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
June 10, 2008
Last Updated
December 3, 2018
Sponsor
Cubist Pharmaceuticals LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00695903
Brief Title
Phase 2 Study of Safety, Efficacy, and Pharmacokinetics of Higher Doses of Daptomycin and Vancomycin in MRSA Bacteremia
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2018
Overall Recruitment Status
Terminated
Why Stopped
terminated due to lack of enrollment
Study Start Date
September 17, 2008 (Actual)
Primary Completion Date
August 24, 2010 (Actual)
Study Completion Date
October 1, 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cubist Pharmaceuticals LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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).
Detailed Description
Patients who meet all inclusion criteria and exhibit none of the exclusion criterial will be randomized to one of two treatment arms: daptomycin Intravenously (IV) 10 mg/kg every 24 hours 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endocarditis, Bacterial, Infective Endocarditis
Keywords
Gram-positive bacterial infections, Staph Aureus, Bacteremia, MRSA, Infective Endocarditis, Right-sided Infective endocarditis, SABIE, SAIE, RIE

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
daptomycin 10 mg/kg
Arm Type
Experimental
Arm Description
Daptomycin 10 mg/kg IV every 24 hours
Arm Title
vancomycin high-dose
Arm Type
Experimental
Arm Description
Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Intervention Type
Drug
Intervention Name(s)
daptomycin
Other Intervention Name(s)
Cubicin, daptomycin for injection
Intervention Description
daptomycin 10 mg/kg IV every 24 hours
Intervention Type
Drug
Intervention Name(s)
vancomycin
Other Intervention Name(s)
vancocin
Intervention Description
Vancomycin 15 mg/kg IV, dosed to maintain trough serum concentrations of 15 to 20 μg/mL
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations
Description
Number of participants with treatment-emergent CPK elevations ≥5 x upper limit of normal (≥1,000 U/L) by the EOT visit.
Time Frame
On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
Title
Number of Participants With Elevated Serum Creatinine
Description
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.
Time Frame
On therapy and up to 3 days post-therapy (treatment duration ranged from 2 to 43 days)
Secondary Outcome Measure Information:
Title
Number of Participants With Treatment Cure at End of Therapy (EOT) Visit
Description
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.
Time Frame
End of Therapy (median day 12 and 6.5 in daptomycin and vancomycin modified intent-to treat population, respectively)
Title
Number of Participants With Treatment Cure at Test of Cure (TOC)/Safety Visit
Description
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.
Time Frame
Test of Cure (TOC) Visit (35 to 49 days post-therapy, approximately week 8)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Pertel, MD
Organizational Affiliation
Cubist Pharmaceuticals LLC
Official's Role
Study Director
Facility Information:
Facility Name
East Carolina University
City
Greenville
State/Province
North Carolina
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php

Learn more about this trial

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

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