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Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection (Bacteremia)

Primary Purpose

Bacteremia

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Vancomycin
Vancomycin
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bacteremia focused on measuring staphylococci

Eligibility Criteria

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

Inclusion Criteria:

  1. Provide signed and dated informed consent. The patient's legally authorized representative (LAR) can provide a signed informed consent for the patient if allowed by local Institutional Review Board/Ethics Committee (IRB/EC) policy.
  2. Is ≥ 18 yrs of age.
  3. If the subject has an intravenous catheter in place then the subject and his/her primary health care provider must agree to have the catheter removed within 5 days of the initial blood culture draw with the exception of those subjects who meet criteria for simple CoNS bacteremia as defined in Table 1. The catheter may be retained in those subjects with simple CoNS bacteremia.
  4. Has blood stream infection defined as at least one blood culture positive for S. aureus or CoNS. In most cases, vancomycin(or other study drug alternative) will have been started prior to randomization. Enrollment windows depend on speciation and clinical classification as follows:

    1. identification of CoNS and classification as simple per Table 1-must be randomized within 3 calendar days of the start of treatment effective for the baseline infecting pathogen
    2. identification of CoNS and classification as uncomplicated per Table 1 must be randomized within 4 calendar days of the start of treatment effective for the baseline infecting pathogen
    3. identification of S. aureus - must be randomized within 12 calendar days of the start of treatment effective for the baseline infecting pathogen
  5. This criterion has been removed
  6. Women of child bearing potential must have a negative urine and/or serum pregnancy test.
  7. All patients of reproductive potential must be abstinent or agree to use double-barrier contraception while receiving study (algorithm based or Standard of Care) therapy.

Exclusion Criteria:

  1. Has known or suspected new complicated staphylococcal infection at the time of enrollment.
  2. Weigh ≥ 200 kg.
  3. Has non-removable intravascular foreign material at the time a positive blood culture was drawn (e.g., intracardiac pacemaker or cardioverter/defibrillator wires, hemodialysis access grafts, cardiac prosthetic valve, valvular support ring). Exception: coronary stents, inferior vena cava (IVC) filters in place > 6 weeks, patients with pacemakers whose baseline infecting pathogen is a CoNS, vascular stents in place for > 6 weeks, non-hemodialysis grafts in place >90 days and hemodialysis grafts not used within past 12 months and not previously infected are eligible for randomization. Arthroplasties and other extravascular devices, e.g. synthetic hernia repair mesh, and non-arthroplasty orthopedic prostheses including pins or plates, are acceptable as long as there are no signs or symptoms of foreign material-related infection at the time of randomization.
  4. This criterion has been removed
  5. Has a moribund clinical condition such that there is a high likelihood of death or cardiac surgery during the next three days.
  6. Has shock or hypotension (supine systolic blood pressure < 80 mmHg) or oliguria (urine output < 20 mL/h) unresponsive to fluids or pressors within four hours.
  7. Has received an investigational antibacterial agent with anti-staphylococcal activity within 30 days prior to randomization.
  8. Has a documented history of significant allergy or intolerance to all protocol-approved antibiotics anticipated to be effective for their infection.
  9. Has an infecting pathogen with confirmed reduced susceptibility to vancomycin (Minimum Inhibitory Concentrations (MIC) > 2 µg/mL) if known. Note: If reduced susceptibility to vancomycin is discovered after enrollment, the patient will be treated with daptomycin (if pathogen is susceptible). Patient will remain in study as appropriate and be evaluated in the Intent to Treat (ITT) analysis, but will be excluded from Protocol Population (PP) analyses.
  10. For S. Aureus patients, is severely neutropenic (absolute neutrophil count < 0.100x103/mm3) or is anticipated to develop severe neutropenia (absolute neutrophil count < 0.100x103/ mm3) during the study treatment period due to prior or planned chemotherapy. CoNS patients with neutropenia are eligible to be enrolled.
  11. This criterion has been removed
  12. Has previously known Human Immunodeficiency Virus (HIV) infection with a nadir CD4+ count of <100 cells/mm3 within the past 12 months
  13. Is considered unlikely to comply with study procedures or to return for scheduled post-treatment evaluations.
  14. Is pregnant or trying to get pregnant, nursing, or lactating.
  15. Has known or suspected septic arthritis, osteomyelitis, pneumonia or other metastatic focus of infection. CoNS patients with pneumonia and not being treated or anticipated to start treatment with antibiotics effective for the baseline infecting pathogen can be included
  16. Has polymicrobial blood stream infection including at least one non-staphylococcal species, except AFTER consultation with the Clinical Medical Monitor at DCRI. Note that it is possible that a subject may not have a known polymicrobial bloodstream infection at the time of randomization, but additional pathogen(s) can subsequently be isolated from the initial blood culture. These patients will be eligible to remain in the trial. Please also note that patients with S. aureus plus CoNS will follow the treatment pathway for S. aureus.
  17. This criterion has been removed.
  18. Is hemodialysis dependent or has end stage renal disease (Creatinine Clearance (CrCl) < 30 cc/min).
  19. Developed Staphylococcus aureus blood stream infection within 72 hours of percutaneous coronary revascularization
  20. Received of any of the following antibiotics for 7 or more of the 10 calendar days immediately preceding the calendar day that the initial positive blood culture was drawn:

    1. If methicillin susceptibility of the isolate is unknown at the time of enrollment: vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either oral or IV administration); quinupristin/dalfopristin; piperacillin/tazobactam; penicillin; nafcillin; oxacillin; cloxacillin; cefazolin, ceftriaxone, ceftaroline, dalbavancin, oritavancin, tedizolid, and levofloxacin or equivalent fluoroquinolone (in either oral or IV administration) Note: ciprofloxacin is not an exclusion criteria.
    2. If the staphylococcal isolate is known to be methicillin resistant: vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either oral or IV administration), quinupristin/dalfopristin, dalbavancin, oritavancin, tedizolid, and ceftaroline.

    Note: patients who have developed bacteremia after at least 7 days of prophylaxis with oral antibiotics have by definition failed prophylaxis and the oral antibiotic can be deemed non-effective for the index bacteremia. Oral antibiotics that have failed as prophylaxis in this manner will not be considered exclusionary or count towards the number of antibiotic days but must be stopped upon randomization

  21. Has previously participated in this study.

Sites / Locations

  • University of Alabama, Birmingham
  • David Geffen School of Medicine UCLA
  • University of Colorado
  • University of Mass
  • Henry Ford Hospital
  • William Beaumont Hospital
  • University of Nebraska Medical Center
  • Albert Einstein College of Medicine
  • Carolina Medical Center
  • Duke University Medical Center
  • Brody School of Medicine at ECU
  • Medical University of South Carolina
  • Greenville Hospital System
  • UT MD Anderson Cancer Center
  • Fundacio Clinic Privada per a la Recera

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Algorithm-determined therapy

Standard of Care

Arm Description

Outcomes

Primary Outcome Measures

Cure Rate
To compare the cure rate at Test of Cure evaluation, between the proposed treatment algorithm and the standard of care therapy.
Number of Participants With Serious Adverse Events
Number of Participants that reported a Serious Adverse Event
Number of Participants With Adverse Events Leading to Study Drug Withdrawal
Number of Participants with an Adverse Event leading to study drug withdrawal
Number of Participants That Changed From Vancomycin to Another Study Antibiotic Due to an Adverse Event
Patient changes from vancomycin or a protocol-approved study antibiotic to another protocol-approved study antibiotic due to AE associated with study drug

Secondary Outcome Measures

Antibiotic Days by Treatment Group
This will be analyzed by evaluating the difference in antibiotic days by treatment group and calculating 95% confidence intervals around the difference in antibiotic days among study patients randomized to algorithm-based treatment vs. among study patients randomized to standard treatment.

Full Information

First Posted
August 28, 2010
Last Updated
December 12, 2017
Sponsor
Duke University
Collaborators
National Institutes of Health (NIH)
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1. Study Identification

Unique Protocol Identification Number
NCT01191840
Brief Title
Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection
Acronym
Bacteremia
Official Title
A Multi-Center, Randomized, Open-Label, Comparative Study to Assess the Safety and Efficacy of a Treatment Algorithm to Reduce the Use of Vancomycin in Adult Patients With Blood Stream Infections Due to Staphylococci
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
February 2011 (undefined)
Primary Completion Date
March 4, 2017 (Actual)
Study Completion Date
March 4, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
National Institutes of Health (NIH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to accurately determine the length of appropriate drug treatment for staphylococcal blood stream infection. The study seeks to address important information about the management of staphylococcal blood stream infections.
Detailed Description
To demonstrate that the clinical efficacy of algorithm-based therapy of patients with staphylococcal blood stream infection is noninferior to current standard of care. PP (per protocol) population: randomized patients EXCLUDING those that: Received a PENS antibiotic -Did not undergo removal of intravascular catheter suspected to be infected. Note that patients with simple CoNS bacteremia may retain the catheter; all other patients should have their catheter(s) removed. -Had blood stream infection with a vancomycin-resistant staphylococcus; or a staphylococcus resistant to protocol-identified alternative drugs if these were used -Discontinued study medication prematurely for reasons other than clinical failure -Did not undergo final TOC assessment -Did not comply with all Patient Inclusion Criteria -Violated any Patient Exclusion Criteria Died within 3 days of randomization Were classified as non-evaluable PPE Population: Patients from the PP population who did not have complicated staphylococcal infection.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bacteremia
Keywords
staphylococci

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
509 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Algorithm-determined therapy
Arm Type
Experimental
Arm Title
Standard of Care
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Vancomycin
Other Intervention Name(s)
Nafcillin, Oxacillin, Cloxacillin, Daptomycin, Cefazolin
Intervention Description
Duration
Intervention Type
Drug
Intervention Name(s)
Vancomycin
Other Intervention Name(s)
Nafcillin, Oxacillin, Cloxacillin, Daptomycin, Cefazolin
Intervention Description
Duration
Primary Outcome Measure Information:
Title
Cure Rate
Description
To compare the cure rate at Test of Cure evaluation, between the proposed treatment algorithm and the standard of care therapy.
Time Frame
Test of cure 2 (up to approximately 42 days)
Title
Number of Participants With Serious Adverse Events
Description
Number of Participants that reported a Serious Adverse Event
Time Frame
Test of cure 2 (up to approximately 42 days)
Title
Number of Participants With Adverse Events Leading to Study Drug Withdrawal
Description
Number of Participants with an Adverse Event leading to study drug withdrawal
Time Frame
Test of cure 2 (up to approximately 42 days)
Title
Number of Participants That Changed From Vancomycin to Another Study Antibiotic Due to an Adverse Event
Description
Patient changes from vancomycin or a protocol-approved study antibiotic to another protocol-approved study antibiotic due to AE associated with study drug
Time Frame
Test of cure 2 (up to approximately 42 days)
Secondary Outcome Measure Information:
Title
Antibiotic Days by Treatment Group
Description
This will be analyzed by evaluating the difference in antibiotic days by treatment group and calculating 95% confidence intervals around the difference in antibiotic days among study patients randomized to algorithm-based treatment vs. among study patients randomized to standard treatment.
Time Frame
Test of cure 2 (up to approximately 42 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Provide signed and dated informed consent. The patient's legally authorized representative (LAR) can provide a signed informed consent for the patient if allowed by local Institutional Review Board/Ethics Committee (IRB/EC) policy. Is ≥ 18 yrs of age. If the subject has an intravenous catheter in place then the subject and his/her primary health care provider must agree to have the catheter removed within 5 days of the initial blood culture draw with the exception of those subjects who meet criteria for simple CoNS bacteremia as defined in Table 1. The catheter may be retained in those subjects with simple CoNS bacteremia. Has blood stream infection defined as at least one blood culture positive for S. aureus or CoNS. In most cases, vancomycin(or other study drug alternative) will have been started prior to randomization. Enrollment windows depend on speciation and clinical classification as follows: identification of CoNS and classification as simple per Table 1-must be randomized within 3 calendar days of the start of treatment effective for the baseline infecting pathogen identification of CoNS and classification as uncomplicated per Table 1 must be randomized within 4 calendar days of the start of treatment effective for the baseline infecting pathogen identification of S. aureus - must be randomized within 12 calendar days of the start of treatment effective for the baseline infecting pathogen This criterion has been removed Women of child bearing potential must have a negative urine and/or serum pregnancy test. All patients of reproductive potential must be abstinent or agree to use double-barrier contraception while receiving study (algorithm based or Standard of Care) therapy. Exclusion Criteria: Has known or suspected new complicated staphylococcal infection at the time of enrollment. Weigh ≥ 200 kg. Has non-removable intravascular foreign material at the time a positive blood culture was drawn (e.g., intracardiac pacemaker or cardioverter/defibrillator wires, hemodialysis access grafts, cardiac prosthetic valve, valvular support ring). Exception: coronary stents, inferior vena cava (IVC) filters in place > 6 weeks, patients with pacemakers whose baseline infecting pathogen is a CoNS, vascular stents in place for > 6 weeks, non-hemodialysis grafts in place >90 days and hemodialysis grafts not used within past 12 months and not previously infected are eligible for randomization. Arthroplasties and other extravascular devices, e.g. synthetic hernia repair mesh, and non-arthroplasty orthopedic prostheses including pins or plates, are acceptable as long as there are no signs or symptoms of foreign material-related infection at the time of randomization. This criterion has been removed Has a moribund clinical condition such that there is a high likelihood of death or cardiac surgery during the next three days. Has shock or hypotension (supine systolic blood pressure < 80 mmHg) or oliguria (urine output < 20 mL/h) unresponsive to fluids or pressors within four hours. Has received an investigational antibacterial agent with anti-staphylococcal activity within 30 days prior to randomization. Has a documented history of significant allergy or intolerance to all protocol-approved antibiotics anticipated to be effective for their infection. Has an infecting pathogen with confirmed reduced susceptibility to vancomycin (Minimum Inhibitory Concentrations (MIC) > 2 µg/mL) if known. Note: If reduced susceptibility to vancomycin is discovered after enrollment, the patient will be treated with daptomycin (if pathogen is susceptible). Patient will remain in study as appropriate and be evaluated in the Intent to Treat (ITT) analysis, but will be excluded from Protocol Population (PP) analyses. For S. Aureus patients, is severely neutropenic (absolute neutrophil count < 0.100x103/mm3) or is anticipated to develop severe neutropenia (absolute neutrophil count < 0.100x103/ mm3) during the study treatment period due to prior or planned chemotherapy. CoNS patients with neutropenia are eligible to be enrolled. This criterion has been removed Has previously known Human Immunodeficiency Virus (HIV) infection with a nadir CD4+ count of <100 cells/mm3 within the past 12 months Is considered unlikely to comply with study procedures or to return for scheduled post-treatment evaluations. Is pregnant or trying to get pregnant, nursing, or lactating. Has known or suspected septic arthritis, osteomyelitis, pneumonia or other metastatic focus of infection. CoNS patients with pneumonia and not being treated or anticipated to start treatment with antibiotics effective for the baseline infecting pathogen can be included Has polymicrobial blood stream infection including at least one non-staphylococcal species, except AFTER consultation with the Clinical Medical Monitor at DCRI. Note that it is possible that a subject may not have a known polymicrobial bloodstream infection at the time of randomization, but additional pathogen(s) can subsequently be isolated from the initial blood culture. These patients will be eligible to remain in the trial. Please also note that patients with S. aureus plus CoNS will follow the treatment pathway for S. aureus. This criterion has been removed. Is hemodialysis dependent or has end stage renal disease (Creatinine Clearance (CrCl) < 30 cc/min). Developed Staphylococcus aureus blood stream infection within 72 hours of percutaneous coronary revascularization Received of any of the following antibiotics for 7 or more of the 10 calendar days immediately preceding the calendar day that the initial positive blood culture was drawn: If methicillin susceptibility of the isolate is unknown at the time of enrollment: vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either oral or IV administration); quinupristin/dalfopristin; piperacillin/tazobactam; penicillin; nafcillin; oxacillin; cloxacillin; cefazolin, ceftriaxone, ceftaroline, dalbavancin, oritavancin, tedizolid, and levofloxacin or equivalent fluoroquinolone (in either oral or IV administration) Note: ciprofloxacin is not an exclusion criteria. If the staphylococcal isolate is known to be methicillin resistant: vancomycin; daptomycin; telavancin; tigecycline; linezolid (in either oral or IV administration), quinupristin/dalfopristin, dalbavancin, oritavancin, tedizolid, and ceftaroline. Note: patients who have developed bacteremia after at least 7 days of prophylaxis with oral antibiotics have by definition failed prophylaxis and the oral antibiotic can be deemed non-effective for the index bacteremia. Oral antibiotics that have failed as prophylaxis in this manner will not be considered exclusionary or count towards the number of antibiotic days but must be stopped upon randomization Has previously participated in this study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vance Fowler, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama, Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
David Geffen School of Medicine UCLA
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80204
Country
United States
Facility Name
University of Mass
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01752
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
William Beaumont Hospital
City
Royal Oak
State/Province
Michigan
ZIP/Postal Code
48073
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Albert Einstein College of Medicine
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Carolina Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28207
Country
United States
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Brody School of Medicine at ECU
City
Greenville
State/Province
North Carolina
ZIP/Postal Code
27834
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Greenville Hospital System
City
Greenville
State/Province
South Carolina
ZIP/Postal Code
29605
Country
United States
Facility Name
UT MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Fundacio Clinic Privada per a la Recera
City
Barcelona
ZIP/Postal Code
08036
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
30264119
Citation
Holland TL, Raad I, Boucher HW, Anderson DJ, Cosgrove SE, Aycock PS, Baddley JW, Chaftari AM, Chow SC, Chu VH, Carugati M, Cook P, Corey GR, Crowley AL, Daly J, Gu J, Hachem R, Horton J, Jenkins TC, Levine D, Miro JM, Pericas JM, Riska P, Rubin Z, Rupp ME, Schrank J Jr, Sims M, Wray D, Zervos M, Fowler VG Jr; Staphylococcal Bacteremia Investigators. Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial. JAMA. 2018 Sep 25;320(12):1249-1258. doi: 10.1001/jama.2018.13155.
Results Reference
derived

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Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection

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