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

Bacteremia Due to Staphylococcus Aureus Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01975662
• Other study ID #: SIDI-MRSA-001
• Status: Terminated
• Phase: Phase 2
• First received: October 29, 2013
• Last updated: April 12, 2016
• Start date: January 2014
• Est. completion date: December 2015

Study information

• Verified date: April 2016
• Source: Singapore General Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: Singapore: Health Sciences Authority
• Study type: Interventional

Clinical Trial 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%.

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

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 14
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 21 Years and older

Eligibility

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.)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bacteremia
• Bacteremia Due to Staphylococcus Aureus

Intervention

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.
• 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.

Locations

Country	Name	City	State
Singapore	Singapore General Hospital	Singapore

Sponsors (2)

Lead Sponsor	Collaborator
Singapore General Hospital	Singapore Clinical Research Institute

Country where clinical trial is conducted

Singapore, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	All cause mortality in the different subtypes of bacteremia	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: Uncomplicated bacteremia; Complicated bacteremia without endocarditis; Right- sided endocarditis; Left sided endocarditis	60 days	No
Other	Rates of clinical failure in the different subtypes of bacteremia	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: Uncomplicated bacteremia; Complicated bacteremia without endocarditis; Right- sided endocarditis; Left sided endocarditis	60 days	No
Primary	All cause mortality	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.	60 days	No
Secondary	Rates of clinical failure	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.	60 days	No
Secondary	Time to microbiological clearance	To compare time to microbiological clearance. Microbiological clearance is defined as two consecutive MRSA negative blood cultures.	60 days	No
Secondary	Rates of nephrotoxicity	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.	60 days	Yes
Secondary	Rates of musculoskeletal toxicity	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.	60 days	Yes
Secondary	The need to stop the study drug due to toxicity	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])	60 days	Yes
Secondary	The need to discontinue study drug due to worsening infection	To evaluate the need to discontinue study drug due to worsening infection while on study treatment.	60 days	No
Secondary	The need for an additional anti-MRSA agent due to worsening infection while on study treatment.	To evaluate the need for an additional anti-MRSA agent due to worsening infection while on study treatment.	60 days	No
Secondary	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.	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.	90 days	Yes
Secondary	Serious adverse events at any time during the study period, whether or not they are thought to be related to the investigation drug.	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.	60 days	Yes