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

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by Singapore General Hospital
Sponsor:
Collaborator:
Singapore Clinical Research Institute
Information provided by (Responsible Party):
Singapore General Hospital
ClinicalTrials.gov Identifier:
NCT01975662
First received: October 29, 2013
Last updated: February 2, 2014
Last verified: February 2014
  Purpose

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%.


Condition Intervention Phase
Bacteremia Due to Staphylococcus Aureus
Drug: Daptomycin
Drug: Vancomycin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Vancomycin Minimum Inhibitory Concentrations

Resource links provided by NLM:


Further study details as provided by Singapore General Hospital:

Primary Outcome Measures:
  • All cause mortality [ Time Frame: 60 days ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Rates of clinical failure [ Time Frame: 60 days ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    To compare time to microbiological clearance. Microbiological clearance is defined as two consecutive MRSA negative blood cultures.

  • Rates of nephrotoxicity [ Time Frame: 60 days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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.


Other Outcome Measures:
  • All cause mortality in the different subtypes of bacteremia [ Time Frame: 60 days ] [ Designated as safety issue: No ]

    To compare rates of all-cause mortality 60 days from the time of index blood culture of daptomycin treatment versus vancomycin treatment in the following subtypes of bacteremia (as per the patient's final diagnosis) defined as follows:

    1. Uncomplicated bacteremia
    2. Complicated bacteremia without endocarditis
    3. Right- sided endocarditis
    4. Left sided endocarditis

  • Rates of clinical failure in the different subtypes of bacteremia [ Time Frame: 60 days ] [ Designated as safety issue: No ]

    To compare rates of clinical failure of daptomycin treatment versus vancomycin treatment in the following subtypes of bacteremia (as per the patient's final diagnosis) defined as follows:

    1. Uncomplicated bacteremia
    2. Complicated bacteremia without endocarditis
    3. Right- sided endocarditis
    4. Left sided endocarditis


Estimated Enrollment: 50
Study Start Date: January 2014
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Daptomycin

Daptomycin will be dosed intravenously at 6-8mg/kg every 24 hours.

Patients with uncomplicated bacteremia will receive a dose of 6mg/kg every 24 hours. Patients with suspected complicated bacteremia or endocarditis, or receipt of at least two doses of vancomycin in the last 90 days (apart from vancomycin received for their current MRSA bacteremia) will receive a dose of 8mg/kg every 24 hours.

In patients with a creatinine clearance less than 30ml/min, or on intermittent or continuous hemodialysis, daptomycin will be dosed at 6-8mg/kg every 48 hours. The same criteria as above applies as to whether they receive 6mg/kg or 8mg/kg every 48hours. Daptomycin will be administered after hemodialysis in patients undergoing intermittent hemodialysis.

Drug: Daptomycin
Duration of treatment will be determined based on the type of bacteremia. Patients with uncomplicated bacteremia will receive a minimum of 14 days antibiotics and those with complicated bacteremia or infective endocarditis will receive a minimum of 28 to 42 days antibiotics from the date that microbiological clearance is achieved.
Other Name: Cubicin
Active Comparator: Vancomycin
Vancomycin will be dosed at 15mg/kg every 12 hours with appropriate dose adjustments by a pharmacist in patients with a creatinine clearance less than 50 ml/min, so as to achieve a vancomycin trough level of 15-20ug/ml.
Drug: Vancomycin
Duration of treatment will be determined based on the type of bacteremia. Patients with uncomplicated bacteremia will receive a minimum of 14 days antibiotics and those with complicated bacteremia or infective endocarditis will receive a minimum of 28 to 42 days antibiotics from the date that microbiological clearance is achieved.
Other Name: Vancomycin Hydrochloride

Detailed Description:

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 arm receiving daptomycin. The primary objective 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 60 days from positive index blood culture. Secondary outcomes include rates of clinical failure, time to microbiological clearance, and rates of nephro- and muscular toxicities in both arms.

If the pilot study proves our hypothesis that indeed , we aim to proceed with a larger scale trial

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age > 21 years.
  • Inpatient at the time of enrolment.
  • MRSA bacteremia due to MRSA isolates with a vancomycin MIC > 1.5 ug/ml.
  • Be prepared to undergo all treatments and procedures, and attend follow-ups as per the trial protocol.

Exclusion Criteria:

  • Allergy to any of the study medications.
  • Pregnant or breastfeeding females.
  • Unable to provide consent or have no legally authorized representatives.
  • Currently enrolled or within the past three months participated in an interventional antibiotic or vaccine trial.
  • >48 hours after MRSA vancomycin MIC > or equal to1.5 ug/ml confirmation by the microbiology laboratory (assessed from time of lab report).
  • Patients on palliative care or with less than 24 hours of life expectancy (as discussed with their primary physicians).
  • Polymicrobial bacteremia [see (a) below].
  • Pneumonia [see (b) below].
  • On treatment with linezolid, tigecycline or ceftaroline immediately prior to enrolment.
  • Previous blood cultures positive for MRSA in the preceding one month.
  • On vancomycin or daptomycin treatment for more than 96 hours prior to enrolment.
  • BSI due to MRSA with vancomycin MIC > or equal to 4 ug/ml.
  • Baseline serum creatine kinase more than 1.5 times the upper limit of normal.
  • Patients with prosthetic heart valves
  • Any other significant condition that would, in the opinion of the investigator, compromise the patient's safety or outcome in the trial.

    1. .Isolation of a significant organism other than MRSA from index blood cultures or blood cultures taken up to two weeks prior to enrolment and/or for which the patient is still on treatment.
    2. .Chest x-ray at baseline consistent with pneumonia AND at least 2 of the following signs and symptoms: New onset or worsening cough, purulent sputum or increased suctioning requirements, dyspnea/tachypnea or respiratory rate > 30/min, hypoxemia or worsening gas exchange as determined by study investigator.)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01975662

Contacts
Contact: Thuan Tong Tan, MBBS, PhD +65-63213479 tan.thuan.tong@sgh.com.sg
Contact: Shirin Kalimuddin, MBBS, MRCP +65-63213479 shirin.kalimuddi@sgh.com.sg

Locations
Singapore
Singapore General Hospital Recruiting
Singapore, Singapore, 169608
Contact: Thuan Tong Tan, MBBS,PhD    +65-63213479    tan.thuan.tong@sgh.com.sg   
Contact: Shirin Kalimuddin, MBBS, MRCP    +65-63213479    shirin.kalimuddin@sgh.com.sg   
Principal Investigator: Thuan Tong Tan, MBBS, PhD         
Sponsors and Collaborators
Singapore General Hospital
Singapore Clinical Research Institute
Investigators
Principal Investigator: Thuan Tong Tan, MBBS, PhD Singapore General Hospital
  More Information

No publications provided by Singapore General Hospital

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Singapore General Hospital
ClinicalTrials.gov Identifier: NCT01975662     History of Changes
Other Study ID Numbers: SIDI-MRSA-001
Study First Received: October 29, 2013
Last Updated: February 2, 2014
Health Authority: Singapore: Health Sciences Authority

Keywords provided by Singapore General Hospital:
MRSA
bacteremia
vancomycin
daptomycin

Additional relevant MeSH terms:
Bacteremia
Bacterial Infections
Infection
Inflammation
Pathologic Processes
Sepsis
Systemic Inflammatory Response Syndrome
Daptomycin
Vancomycin
Anti-Bacterial Agents
Anti-Infective Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014