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.
Brief Title
Treatment Algorithm to Reduce the Use of Vancomycin in Adults With Blood Stream Infection
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.
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.
Completion Date
Completion Date Type
Actual
Conditions
Bacteremia
Eligibility Criteria
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.
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.
Inclusion Criteria
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.
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.
Gender
All
Gender Based
false
Keywords
staphylococci
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01191840
Org Class
Other
Org Full Name
Duke University
Org Study Id
Pro00025497
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
To compare the cure rate at Test of Cure evaluation, between the proposed treatment algorithm and the standard of care therapy.
Outcome Measure
Cure Rate
Outcome Time Frame
Test of cure 2 (up to approximately 42 days)
Outcome Description
Number of Participants that reported a Serious Adverse Event
Outcome Measure
Number of Participants With Serious Adverse Events
Outcome Time Frame
Test of cure 2 (up to approximately 42 days)
Outcome Description
Number of Participants with an Adverse Event leading to study drug withdrawal
Outcome Measure
Number of Participants With Adverse Events Leading to Study Drug Withdrawal
Outcome Time Frame
Test of cure 2 (up to approximately 42 days)
Outcome Description
Patient changes from vancomycin or a protocol-approved study antibiotic to another protocol-approved study antibiotic due to AE associated with study drug
Outcome Measure
Number of Participants That Changed From Vancomycin to Another Study Antibiotic Due to an Adverse Event
Outcome Time Frame
Test of cure 2 (up to approximately 42 days)
Secondary Ids
Secondary Id
DMID Protocol Number: 09-0080
Secondary Outcomes
Outcome 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.
Outcome Time Frame
Test of cure 2 (up to approximately 42 days)
Outcome Measure
Antibiotic Days by Treatment Group
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Paul Riska
Investigator Email
priska@montefiore.org
Investigator Phone
718-020-6494