Clinical trial NCT05893147: BALANCE+ Vanguard Phase
Official title: BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Gram-negative Bacteremia
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2023-06-07
Enrollment: 174
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 72 in the overall platform AND at least 12 in each domain.
Primary purpose: OTHER

Brief summary: The goal of the BALANCE+ clinical trial is to transform random care to randomized care for patients with Gram negative bloodstream infections to inform best treatment approaches and optimize outcomes.

BALANCE+, a perpetual platform trial, will efficiently answer multiple questions that are important for hospitalized patients with Gram negative bloodstream infections.

Detailed description: Bloodstream infections (BSIs) are common and lethal, ranking among the top 7 causes of death, with 600,000 cases and 90,000 deaths per year in North America, and 1.2 Million cases and 150,000 deaths per year in Europe. Despite being a leading cause of death worldwide, bloodstream infections remain understudied. Treatment approaches are complicated by rising rates of antimicrobial resistance and declining new drug development.

BALANCE+ provides a platform upon which to answer multiple pressing cross-cutting questions for patients with Gram negative bloodstream infections, including the concept of de-escalating antibiotic spectrum, optimal transition to oral antibiotics, and the role for routine follow up blood culture testing. The trial will also include a syndrome-specific question of whether to remove or retain a central vascular catheter, and a pathogen-specific question of whether cephalosporins are sufficient for patients with low-risk AmpC organisms. As each question is answered, optimal therapies will be adopted into usual care, and new questions will be introduced into the platform of the trial. The evidence generated by BALANCE+ will improve cure for this vulnerable patient population.

Eligibility criteria: PLATFORM INCLUSION CRITERIA

1. admitted to a participating hospital
2. positive blood culture with Gram negative (GN) bacterium

PLATFORM EXCLUSION CRITERIA

1. patient's goals of care are for palliation with no active treatment
2. moribund patient, not expected to survive \> 72 hours

DOMAIN SPECIFIC INCLUSION AND EXCLUSION CRITERIA

(A) DE-ESCALATION VS. NO DE-ESCALATION DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform

Exclusion Criteria

1. receiving an empiric antibiotic regimen at the time of blood culture finalization to which the GN pathogen(s) are not sensitive
2. carbapenem-resistance (so that patients will not need to remain on reserve-use agents)
3. no de-escalation option due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. other relevant reason
4. patients with a suspected or proven polymicrobial source of infection

(B) BETA-LACTAM VS. NON-BETA-LACTAM ORAL/ENTERAL TREATMENT DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform
2. initially treated with intravenous antibiotics, but clinical team transitioning patient to oral/enteral antibiotic within 7 days of starting treatment

Exclusion Criteria

1. enrolled in an arm of another BALANCE+ platform domain which limits the use of oral/enteral therapy

   - no-de-escalation arm
2. no non-beta-lactam options due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. other relevant reason
3. no beta-lactam options due to any or all of

   i. resistance ii. allergies iii. medical contraindications iv. drug-drug interaction risk v. other relevant reason

(C) CENTRAL VASCULAR CATHETER REPLACEMENT DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform
2. has an indwelling central vascular catheter that was already in place within the 48-hour period before the onset of bloodstream infection (i.e. is not a new catheter placed within 48 hours of the onset of infection)

Exclusion Criteria

1. patient has no ongoing need for a central vascular catheter
2. patient has definite indication for central vascular catheter removal

   1. ongoing septic shock with definite/probable line source
   2. concomitant S. aureus bacteremia
   3. concomitant candidemia
   4. local suppurative signs (severe redness, warmth, pain, swelling or fluctuance/collection) necessitating catheter removal, or other clinical evidence of infected line (e.g. imaging/echocardiographic findings)
   5. definite alternative source of GN BSI

(D) LOW-RISK AmpC DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform
2. positive blood culture with GN bacterium, of the following species

   1. Serratia spp.
   2. Morganella spp.
   3. Providencia spp.
   4. Proteus spp. other than P.mirabilis
   5. organism is sensitive to ceftriaxone

Exclusion Criteria

1. severe allergy to beta-lactams (eg, type 4 hypersensitivity reaction or DRESS)
2. baseline phenotypic resistance to ceftriaxone

(E) FOLLOW UP BLOOD CULTURE DOMAIN

Inclusion Criteria

1. included in BALANCE+ platform

Exclusion Criteria

1. patient already discharged home prior to day 4
2. definite indication for repeat blood culture testing

   1. concomitant Staph. aureus bacteremia
   2. concomitant Candidemia
   3. clinical suspicion for infective endocarditis (e.g., presence of prosthetic valve, implantable cardiac device)

Primary outcomes:
measure: Recruitment rate (co-primary outcomes of BALANCE+ vanguard phase)
timeFrame: 1 year
measure: Protocol adherence (co-primary outcomes of BALANCE+ vanguard phase)
timeFrame: 1 year
measure: De-escalation versus no de-escalation domain
timeFrame: 90 days
measure: Oral beta-lactam versus non beta-lactam domain
timeFrame: 90 days
measure: Central vascular catheter retention versus replacement domain
timeFrame: 90 days
measure: Low-risk AmpC domain
timeFrame: 90 days
measure: Follow-up blood culture domain
timeFrame: 90 days
Secondary outcomes:
measure: 90-day mortality
timeFrame: 90 days
measure: 90-day reinfection
timeFrame: 90 days
measure: 90-day all cause readmission
timeFrame: 90 days
measure: 90-day AMR colonization/infection
timeFrame: 90 days
measure: 90-day Clostridioides difficile infection (CDI)
timeFrame: 90 days
measure: 30-day mortality
timeFrame: 30 days
measure: 60-day mortality
timeFrame: 60 days
Other outcomes:
Locations:
city: Calgary
country: Canada
facility: Foothills Hospital
state: Alberta
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: Saint John's
country: Canada
facility: Eastern Regional Health Authority
state: Newfoundland and Labrador
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
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: University Health Network
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Nick Daneman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre
name: Rob Fowler, MD
role: PRINCIPAL_INVESTIGATOR
References: