Clinical trial NCT03005145: Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness
Official title: Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness: Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Bacteremia
Intensive Care
Critically Ill
Sepsis
Mortality
Antimicrobial
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2016-12-29
Enrollment: 3622
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 adequately powered randomized trial evidence is lacking for the treatment of patients with bloodstream infections caused by a wide spectrum of organisms.

Detailed description: Bloodstream infections are a common and serious problem, 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, Clostridioides difficile infection, increased costs, and spiralling 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. BALANCE 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, Investigators completed a pilot trial in ICU patients to establish the feasibility of the research design, and to optimize the definitive trial. Investigators also completed a pilot trial of non-ICUs patients to test the feasibility, compare the patient population in two settings and to assess the reasonableness of expanding the main BALANCE Trial to non-ICU wards. The overall recruitment rate of the non-ICU ward pilot RCT exceeded the recruitment rate in the BALANCE ICU pilot RCT with a protocol adherence of 90%. The results of this pilot were used to estimate the necessary sample size recalculation, after merging the BALANCE ward trial with the BALANCE main trial, with the principle of maintaining an equal to smaller non-inferiority margin by the trial's completion. With the completion of this pilot RCT, the eligibility criteria for the BALANCE trial are also modified to broaden the inclusion of all bacteremic patients admitted to hospital. By defining the duration of treatment for bloodstream infections, BALANCE 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 hospitalized 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. Participants from the vanguard BALANCE pilot RCTs will be included in the BALANCE main RCT, and participating Canadian sites will continue to enrol patients. BALANCE international collaborators include New Zealand, Australia, Saudi Arabia, the United States, Israel and Switzerland.

Eligibility criteria: Inclusion Criteria:

1. Patient is in ICU or non-ICU ward 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 (post major vessel repair with synthetic material) (note: coronary artery stents are not an exclusion)
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 (e.g. infected pacemaker, prosthetic joint infection, ventriculoperitoneal shunt infection etc.) (note: central venous catheters, including tunneled central intravenous catheter, and urinary catheters are not excluded unless the treating clinical team does not have equipoise for enrollment and randomization to either group)
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.
8. Blood culture grows rare bacterial pathogens requiring prolonged treatment (e.g. Mycobacteria spp., Nocardia spp., Actinomyces spp., Brucella spp., Burkholderia pseudomallei)

Primary outcomes:
measure: 90 day survival
timeFrame: 90 days from index blood culture
Secondary outcomes:
measure: Hospital mortality
timeFrame: Expected average of 4 weeks assessed upto one year
measure: ICU mortality
timeFrame: Expected average of 2 weeks assessed upto one year
measure: Relapse rates of bacteremia with the same organism
timeFrame: Upto 30 days after adequate antibiotic treatment
measure: Antibiotic allergy and adverse events
timeFrame: Upto 30 days from start of antibiotic treatment
measure: Rates of C. difficile infection in hospital
timeFrame: Upto 30 days after index blood culture collection date
measure: Rates of secondary nosocomial infection/colonization with antimicrobial resistant organisms in hospital
timeFrame: Upto 30 days after index blood culture collection date
measure: ICU length of stay
timeFrame: Expected for an average of 30 days assessed up to 1 year
measure: Hospital length of stay
timeFrame: Expected for an average of 30 days assessed up to 1 year
measure: Mechanical ventilation duration
timeFrame: Expected for an average of 30 days
measure: Antibiotic free days
timeFrame: Upto 30 days after adequate antibiotic treatment
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU School of Medicine
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Bankstown
country: Australia
facility: Bankstown Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St. George Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital ICU
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Ballarat
country: Australia
facility: Ballarat Hospital
state: Victoria
city: Bendigo
country: Australia
facility: Bendigo Hospital
state: Victoria
city: Berwick
country: Australia
facility: Casey Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Dandenong
country: Australia
facility: Dandenong Hospital- Monash Health
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Langwarrin
country: Australia
facility: Peninsula Private Hospital
state: Victoria
city: Malvern
country: Australia
facility: Cabrini Health
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
city: Subiaco
country: Australia
facility: St John of God Hospital
state: Western Australia
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Lions Gate Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Royal Columbian Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Saint John's
country: Canada
facility: Eastern Regional Health Authority
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Queen Elizabeth II Hospital
state: Nova Scotia
city: Brampton
country: Canada
facility: William Osler Health System
state: Ontario
city: Hamilton
country: Canada
facility: Brantford General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton General Hospital
state: Ontario
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare
state: Ontario
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Mississauga
country: Canada
facility: Trillium Health Partners
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Michael Garron Hospital
state: Ontario
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: St. Joseph's Health Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital
state: Ontario
city: Montreal
country: Canada
facility: Centre hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Montreal
country: Canada
facility: Hospital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Hospitalier Régional de Trois-Rivières
state: Quebec
city: Montreal
country: Canada
facility: Montreal General Hospital
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec
state: Quebec
city: Québec
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Université de Sherbrooke
state: Quebec
city: Quebec
country: Canada
facility: Centre hospitalier affilié universitaire de Québec
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
state: Tel Aviv
city: Tel HaShomer
country: Israel
facility: Sheba Medical Center
state: Tel Aviv
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Auckland
country: New Zealand
facility: Middlemore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: New Plymouth
country: New Zealand
facility: Taranaki Hospital
city: Rotorua
country: New Zealand
facility: Rotorua Hospital
city: Wellington
country: New Zealand
facility: Wellington Hospital
city: Jeddah
country: Saudi Arabia
facility: King Faisal Specialist Hospital & Research Centre
city: Riyadh
country: Saudi Arabia
facility: King Abdulaziz Medical City
city: Bern
country: Switzerland
facility: University hospital Bern
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Nick Daneman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Daneman N, Rishu AH, Pinto RL, Arabi YM, Cook DJ, Hall R, McGuinness S, Muscedere J, Parke R, Reynolds S, Rogers B, Shehabi Y, Fowler RA; Canadian Critical Care Trials Group. Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) randomised clinical trial: study protocol. BMJ Open. 2020 May 11;10(5):e038300. doi: 10.1136/bmjopen-2020-038300.