BALANCE: Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness

• Sponsor: Sunnybrook Health Sciences Centre (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT03005145
• Collaborator: (none)
• Enrollment: 3,622
• Locations: 51
• Arms: 2
• Anticipated Duration (Months): 60.2
• Patients Per Site: 71
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

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.	N/A

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 3622 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: Feb 24, 2017
• Anticipated Primary Completion Date: Mar 1, 2022
• Anticipated Study Completion Date: Mar 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 90 day survival [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

1. 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)

1. 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.

2. Patient has a positive blood culture with Staphylococcus aureus or Staphylococcus lugdunensis

3. Patient has a positive blood culture with Candida spp. or other fungal species.

4. Blood culture grows rare bacterial pathogens requiring prolonged treatment (e.g. Mycobacteria spp., Nocardia spp., Actinomyces spp., Brucella spp., Burkholderia pseudomallei)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU School of Medicine	New York	New York	United States	10016
2	Cleveland Clinic	Cleveland	Ohio	United States	44195
3	Cabrini Health	Melbourne		Australia
4	Dandenong Hospital- Monash Health	Melbourne		Australia
5	Monash Medical Centre	Melbourne		Australia
6	St Vincent's Hospital	Sydney		Australia
7	Westmead Hospital	Sydney		Australia
8	Foothills Hospital	Calgary	Alberta	Canada
9	Peter Lougheed Centre	Calgary	Alberta	Canada
10	University of Alberta Hospital	Edmonton	Alberta	Canada
11	Royal Columbian Hospital	Vancouver	British Columbia	Canada
12	St. Paul's Hospital	Vancouver	British Columbia	Canada
13	Vancouver General Hospital	Vancouver	British Columbia	Canada
14	St. Boniface Hospital	Winnipeg	Manitoba	Canada
15	Queen Elizabeth II Hospital	Halifax	Nova Scotia	Canada
16	William Osler Health System	Brampton	Ontario	Canada
17	Brantford General Hospital	Hamilton	Ontario	Canada
18	Hamilton General Hospital	Hamilton	Ontario	Canada
19	St. Joseph's Healthcare	Hamilton	Ontario	Canada
20	Kingston General Hospital	Kingston	Ontario	Canada
21	London Health Sciences Centre	London	Ontario	Canada
22	Trillium Health Partners	Mississauga	Ontario	Canada
23	The Ottawa Hospital	Ottawa	Ontario	Canada
24	Niagara Health System	St. Catharines	Ontario	Canada
25	Health Sciences North	Sudbury	Ontario	Canada
26	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N3M5
27	Mount Sinai Hospital	Toronto	Ontario	Canada
28	North York General Hospital	Toronto	Ontario	Canada
29	St. Joseph's Health Centre	Toronto	Ontario	Canada
30	St. Michael's Hospital	Toronto	Ontario	Canada
31	Toronto Western Hospital	Toronto	Ontario	Canada
32	Centre hospitalier de l'Université de Montréal (CHUM)	Montreal	Quebec	Canada
33	Hospital Maisonneuve-Rosemont	Montreal	Quebec	Canada
34	Hospitalier Régional de Trois-Rivières	Montreal	Quebec	Canada
35	Montreal General Hospital	Montreal	Quebec	Canada
36	Institut universitaire de cardiologie et de pneumologie de Québec	Québec	Quebec	Canada
37	Université de Sherbrooke	Sherbrooke	Quebec	Canada
38	Vancouver Island Health	Victoria	Vancouver	Canada
39	Royal Victoria Hospital	Qc		Canada
40	Centre hospitalier affilié universitaire de Québec	Quebec		Canada
41	Rabin Medical Center	Petah Tikva		Israel
42	Auckland City Hospital	Auckland		New Zealand
43	Middlemore Hospital	Auckland		New Zealand
44	Christchurch Hospital	Christchurch		New Zealand
45	Waikato Hospital	Hamilton		New Zealand
46	Taranaki Hospital	New Plymouth		New Zealand
47	Rotorua Hospital	Rotorua		New Zealand
48	Wellington Hospital	Wellington		New Zealand
49	King Faisal Specialist Hospital & Research Centre	Jeddah		Saudi Arabia
50	King Abdulaziz Medical City	Riyadh		Saudi Arabia
51	University hospital Bern	Bern		Switzerland

Sponsors and Collaborators

• Sunnybrook Health Sciences Centre

Investigators

• Principal Investigator: Nick Daneman, MD, Sunnybrook Health Sciences Centre

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Sunnybrook Health Sciences Centre
• ClinicalTrials.gov Identifier: NCT03005145
• Other Study ID Numbers: 0796
• First Posted: Dec 29, 2016
• Last Update Posted: Sep 24, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Bacteremia; Critical Illness; Anti-Bacterial Agents; Antibiotics, Antitubercular

Study Results

No Results Posted as of Sep 24, 2021