Clinical Trial: Vancomycin Versus Daptomycin for the Treatment of Methicillin Resistant Staphylococcus Aureus (MRSA) Bacteremia

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A Multi-centre Open Label Randomized Controlled Phase IIB Trial Comparing Vancomycin Versus Daptomycin for the Treatment of MRSA Bacteremia Due to Isolates With High Vanco

Brief Summary:

The aim of this study is to compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of methicillin resistant staphylococcus aureus (MRSA) bloodstream infections (BSI) due to isolates with high vancomycin minimum inhibitory concentrations (MIC) (i.e. > or equal to 1.5 ug/ml) in terms of reducing all-cause mortality.

Our secondary aim is to compare clinical failure rates of daptomycin treatment versus vancomycin treatment and to compare time to microbiological clearance in patients treated with daptomycin versus those treated with vancomycin.

Our primary hypothesis is that Daptomycin treatment is superior to vancomycin treatment in reducing mortality from BSIs due to MRSA with high vancomycin MIC from 25% to 10%.


Detailed Summary:

Introduction/Clinical Significance Vancomycin is the standard first-line treatment for methicillin resistant Staphylococcus aureus (MRSA) bacteremia. In recent years however, there has been an increase in the number of MRSA isolates with high vancomycin minimum inhibitory concentrations (MIC). Recent consensus guidelines recommend clinicians consider using alternative agents such as daptomycin for MRSA infection when the vancomycin MIC is greater than 1 ug/ml. To date however, there has been no head to head randomized trial comparing the safety and efficacy of daptomycin and vancomycin in the treatment of blood stream infections (BSIs) due to MRSA with high vancomycin MICs.

Specific Aims:

Our primary aim is to compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of MRSA BSIs due to isolates with high vancomycin MICs (i.e. > or equal to 1.5 ug/mL) in terms of reducing all-cause mortality.

Our secondary aim is to compare clinical failure rates of daptomycin treatment versus vancomycin treatment and to compare time to microbiological clearance in patients treated with daptomycin versus those treated with vancomycin.

Hypothesis:

Daptomycin treatment is superior to vancomycin treatment in reducing mortality from BSIs due to MRSA with high vancomycin MIC from 25% to 10%.

Methodology We will conduct a prospective open label randomized controlled phase 2B pilot study in 3 major Singaporean hospitals, with balanced treatment assignments within each hospital achieved by permuted block randomization. There will be 21 subjects per arm, with the control arm receiving vancomycin and the experimental a
Sponsor: Singapore General Hospital

Current Primary Outcome: All cause mortality [ Time Frame: 60 days ]

To compare the efficacy of daptomycin treatment versus vancomycin treatment in the treatment of MRSA BSIs due to isolates with high vancomycin MICs (i.e. > or equal to 1.5 ug/L) in terms of reducing all-cause mortality 60 days from the time of index blood culture.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Rates of clinical failure [ Time Frame: 60 days ]

    Our secondary aims are:

    1.To compare the rates of 'clinical failure' as per the following definitions:

    i.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture, microbiologic failure and/or a recurrence of MRSA BSI.

    ii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as microbiologic failure and/or a recurrence of MRSA BSI.

    iii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture and/or microbiologic failure.

  • Time to microbiological clearance [ Time Frame: 60 days ]
    To compare time to microbiological clearance. Microbiological clearance is defined as two consecutive MRSA negative blood cultures.
  • Rates of nephrotoxicity [ Time Frame: 60 days ]
    To evaluate nephrotoxicity in both treatment arms. Nephrotoxicity will be defined as an increase in the serum creatinine level of 50umol/L from baseline or 50% above baseline throughout the course of the study, in the absence of an alternative explanation.
  • Rates of musculoskeletal toxicity [ Time Frame: 60 days ]
    To evaluate musculoskeletal toxicity in both treatment arms as defined by a rise in creatine kinase (CK) of 5 times the upper limit of normal during the course of the study.
  • The need to stop the study drug due to toxicity [ Time Frame: 60 days ]
    To evaluate the need to stop the study drug due to toxicity (as defined by Common Terminology Criteria for Adverse Events version 4.03 [CTCAE])
  • The need to discontinue study drug due to worsening infection [ Time Frame: 60 days ]
    To evaluate the need to discontinue study drug due to worsening infection while on study treatment.
  • The need for an additional anti-MRSA agent due to worsening infection while on study treatment. [ Time Frame: 60 days ]
    To evaluate the need for an additional anti-MRSA agent due to worsening infection while on study treatment.
  • Adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit. [ Time Frame: 90 days ]
    To compare adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit.
  • Serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug. [ Time Frame: 60 days ]
    To assess the occurrence of serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.


Original Secondary Outcome:

  • Rates of clinical failure [ Time Frame: 60 days ]

    Our secondary aims are:

    1.To compare the rates of 'clinical failure' as per the following definitions:

    i.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture, microbiologic failure and/or a recurrence of MRSA BSI.

    ii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as microbiologic failure and/or a recurrence of MRSA BSI.

    iii.To compare clinical failure rates of daptomycin treatment versus vancomycin treatment defined as a composite of all-cause mortality 60 days from index blood culture and/or microbiologic failure.

  • Time to microbiological clearance [ Time Frame: 60 days ]
    To compare time to microbiological clearance. Microbiological clearance is defined as two consecutive MRSA negative blood cultures.
  • Rates of nephrotoxicity [ Time Frame: 60 days ]
    To evaluate nephrotoxicity in both treatment arms. Nephrotoxicity will be defined as an increase in the serum creatinine level of 50umol/L from baseline or 50% above baseline throughout the course of the study, in the absence of an alternative explanation.
  • Rates of musculoskeletal toxicity [ Time Frame: 60 days ]
    To evaluate musculoskeletal toxicity in both treatment arms as defined by a rise in creatine kinase of 5 times the upper limit of normal during the course of the study.
  • The need to stop the study drug due to toxicity [ Time Frame: 60 days ]
    To evaluate the need to stop the study drug due to toxicity (as defined by Common Terminology Criteria for Adverse Events version 4.03 (CTCAE)
  • The need to discontinue study drug due to worsening infection [ Time Frame: 60 days ]
    To evaluate the need to discontinue study drug due to worsening infection while on study treatment.
  • The need for an additional anti-MRSA agent due to worsening infection while on study treatment. [ Time Frame: 60 days ]
    To evaluate the need for an additional anti-MRSA agent due to worsening infection while on study treatment.
  • Adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit. [ Time Frame: 90 days ]
    To compare adverse events in both treatment arms up to 60 days from index culture or 30 days post last study dose if later than the 60 day visit.
  • Serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug. [ Time Frame: 60 days ]
    To assess the occurrence of serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.


Information By: Singapore General Hospital

Dates:
Date Received: October 29, 2013
Date Started: January 2014
Date Completion:
Last Updated: April 12, 2016
Last Verified: April 2016