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Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE)

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ClinicalTrials.gov Identifier: NCT03005145
Recruitment Status : Recruiting
First Posted : December 29, 2016
Last Update Posted : June 24, 2019
Sponsor:
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:
The World Health Organization, U.S. Centers for Disease Control and Prevention, Association of Medical Microbiology and Infectious Diseases (AMMI) Canada, and Health Canada have all declared antimicrobial resistance a global threat to health, based on rapidly increasing resistance rates and declining new drug development. Up to 30-50% of antibiotic use is inappropriate, and excessive durations of treatment are the greatest contributor to inappropriate use. Shorter duration treatment (≤7 days) has been shown in meta-analyses to be as effective as longer antibiotic treatment for a range of mild to moderate infections. A landmark trial in critically ill patients with ventilator-associated pneumonia showed that mortality and relapse rates were non-inferior in patients who received 8 vs 15 days of treatment. Similar randomized trial evidence is lacking for the treatment of patients with bloodstream infection, which affects 15% of critically ill patients, and an estimated 50,000 Canadians per year.

Condition or disease Intervention/treatment Phase
Bacteremia Intensive Care Critically Ill Sepsis Mortality Antimicrobial Other: 7 days of adequate antibiotic treatment Other: 14 days of adequate antibiotic treatment. Not Applicable

Detailed Description:

Bloodstream infections are a common and serious problem, affecting 15% of critically ill patients, increasing length of hospital stay by 2-3 weeks, adding $25,000-40,000 in excess hospital costs, and tripling the risk of death. At the same time, antibiotic overuse is also a common and serious problem, in that 30-50% of antibiotic use is unnecessary or inappropriate, and results in avoidable drug side effects such as kidney failure, Clostridium difficile infection, increased costs, and spiraling antibiotic resistance rates. The greatest contributor to antibiotic overuse is excessive durations of treatment.

Extensive research has demonstrated that shorter duration antibiotic treatment (less or equal to 7 days) is as effective as longer duration treatment for a variety of infectious diseases, but this question has not been directly studied in the setting of bloodstream infection. Our team's systematic review of the medical literature, national survey of Canadian infectious diseases and critical care physicians, multicentre retrospective study and BALANCE pilot RCT, all support the need for a randomized controlled trial comparing shorter (7 days) versus longer (14 days) antibiotic therapy for bloodstream infections. Prior to performing the main trial, we completed a pilot trial to establish the feasibility of the research design, and to optimize the definitive trial. By defining the duration of treatment for bloodstream infections, our research program will help maximize the clinical cure of individual patients, while minimizing their risk of drug side effects, C. difficile, and antibiotic resistance. Since this intervention would require no new technology, and would reduce (rather than increase) health care costs, it would offer immediate benefits to patients and the healthcare system.

The BALANCE RCT will randomize critically ill patients with bloodstream infection to 7 versus 14 days of adequate antibiotic treatment; the antibiotic drugs, doses, routes and interval will be left to the discretion of the treating team. Although placebo controls are not feasible, prolonged allocation concealment to day 7 will be used to mitigate selection bias. The primary analysis will assess whether 7 days is associated with non-inferior 90 day survival as compared to 14 days of treatment. Patients from the vanguard BALANCE pilot RCT will be included in the BALANCE main RCT, and participating Canadian sites will continue to enrol patients (ultimately 20-25 Canadian sites will be included). BALANCE international collaborators in New Zealand, Australia, Saudi Arabia, the United States, France and Germany are working towards inclusion of sites, to facilitate target sample size recruitment within 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 3598 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness: Randomized Controlled Trial
Actual Study Start Date : February 24, 2017
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antibiotics

Arm Intervention/treatment
Active Comparator: Short duration (7 days)
Patients in 7 day arm will receive adequate antibiotics until the end of day 7 only
Other: 7 days of adequate antibiotic treatment
The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia

Active Comparator: Long duration (14 days)
Patients in 14 day arm will receive adequate antibiotics until the end of day 14 only
Other: 14 days of adequate antibiotic treatment.
The choice of treatment including type, dose, route and interval of antibiotic will be left at the discretion of treating team as long as it is appropriate for the bacteremia




Primary Outcome Measures :
  1. 90 day survival [ Time Frame: 90 days from index blood culture ]
    Survival at 90-days recorded as alive or dead at day 90 following index positive blood culture


Secondary Outcome Measures :
  1. Hospital mortality [ Time Frame: Expected average of 4 weeks assessed upto one year ]
    Recorded as alive or dead at hospital discharge following index positive blood culture

  2. ICU mortality [ Time Frame: Expected average of 2 weeks assessed upto one year ]
    Recorded as alive or dead at ICU discharge following index positive blood culture

  3. Relapse rates of bacteremia with the same organism [ Time Frame: Upto 30 days after adequate antibiotic treatment ]
    Defined as the recurrence of bacteremia due to original infecting organism (same Genus and species) after documentation of negative blood cultures or clinical improvement and within 30 days after completing course of adequate antimicrobial therapy.

  4. Antibiotic allergy and adverse events [ Time Frame: Upto 30 days from start of antibiotic treatment ]

    Effect of medication on body that produces the allergic reaction to a medication like:

    • Hives
    • Itching of the skin or eyes
    • Skin rash
    • Swelling of the lips, tongue, or face
    • Wheezing
    • Organ toxicity

  5. Rates of C. difficile infection in hospital [ Time Frame: Upto 30 days after index blood culture collection date ]
    Defined as a positive PCR or ELISA test for Clostridium difficile toxin in the context of diarrhea within hospital of bacteremia diagnosis.

  6. Rates of secondary nosocomial infection/colonization with antimicrobial resistant organisms in hospital [ Time Frame: Upto 30 days after index blood culture collection date ]
    Colonized or infected with at least one highly-resistant microorganism during their hospital stay

  7. ICU length of stay [ Time Frame: Expected for an average of 30 days assessed up to 1 year ]
    Defined as the duration between index blood culture and discharge from the ICU for a consecutive 48-hour period

  8. Hospital length of stay [ Time Frame: Expected for an average of 30 days assessed up to 1 year ]
    Defined as the duration between index blood culture and discharge date from hospital

  9. Mechanical ventilation duration [ Time Frame: Expected for an average of 30 days ]
    Defined as the number of consecutive days receiving invasive (via an endotracheal tube or tracheostomy), or non-invasive (via a facemask, nasal mask, or helmet) ventilation

  10. Antibiotic free days [ Time Frame: Upto 30 days after adequate antibiotic treatment ]
    Defined as the number of days during the 28 days after the start of adequate antibiotics in which patients did not receive any antibiotics.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patient is in ICU or under the care of ICU physician at the time the blood culture is drawn or reported as positive.
  2. Patient has a positive blood culture with pathogenic bacteria.

Exclusion Criteria:

  1. Patient already enrolled in the trial
  2. Patient has severe immune system compromise, as defined by: absolute neutrophil count <0.5x109/L; or is receiving immunosuppressive treatment for solid organ or bone marrow or stem cell transplant
  3. Patient has a prosthetic heart valve or synthetic endovascular graft
  4. Patient has documented or suspected syndrome with well-defined requirement for prolonged treatment:

    i) infective endocarditis; ii) osteomyelitis/septic arthritis; iii) undrainable/undrained abscess; iv) unremovable/unremoved prosthetic-associated infection

  5. Patient has a single positive blood culture with a common contaminant organism according to Clinical Laboratory & Standards Institute (CLSI) Guidelines: coagulase negative staphylococci; or Bacillus spp.; or Corynebacterium spp.; or Propionobacterium spp.; or Aerococcus spp.; or Micrococcus spp.
  6. Patient has a positive blood culture with Staphylococcus aureus or Staphylococcus lugdunensis
  7. Patient has a positive blood culture with Candida spp. or other fungal species.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03005145


Contacts
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Contact: Nick Daneman, MD 4164806100 ext 2791 nick.daneman@sunnybrook.ca
Contact: Robert A Fowler, MD 4164806100 ext 7471 rob.fowler@sunnybrook.ca

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Sponsors and Collaborators
Sunnybrook Health Sciences Centre
Investigators
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Principal Investigator: Nick Daneman, MD Sunnybrook Health Sciences Centre

Additional Information:
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Responsible Party: Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT03005145     History of Changes
Other Study ID Numbers: 0796
First Posted: December 29, 2016    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Anti-Bacterial Agents
Antibiotics, Antitubercular
Anti-Infective Agents
Antitubercular Agents
Bacteremia
Critical Illness
Disease Attributes
Pathologic Processes
Bacterial Infections
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation