BALANCE+ Vanguard Phase

Gram-negative Bacteremia Clinical Trial

— BALANCE+  

Official title:

BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05893147
• Other study ID #: 4369
• Status: Recruiting
• Phase: N/A
• Start date: August 26, 2023
• Est. completion date: July 30, 2027

Study information

• Verified date: May 2024
• Source: Sunnybrook Health Sciences Centre
• Contact: Asgar Rishu, MBBS
• Phone: 4164806100
• Email: asgar.rishu[@]sunnybrook.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: July 30, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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)

Related Conditions & MeSH terms

• Bacteremia
• Gram-negative Bacteremia

Intervention

Other:
• De-escalation VS No De-escalation
No de-escalation group: continue to receive the same antibiotic that was started initially (as long as it is confirmed to be effective based on the blood culture sensitivity result) De-escalation group: switched to narrower spectrum antibiotic.
• Oral beta-lactams VS non beta-lactams
Beta-lactam antibiotic: This can be ciprofloxacin, moxifloxacin, levofloxacin or trimethoprim-sulfamethoxazole. Non beta-lactam antibiotic: This can be, but not limited to, amoxicillin, amoxicillin-clavulanate, cephalexin, cefadroxil, or cefixime.
• Central vascular catheter retention VS Central vascular catheter replacement
Central vascular catheter replacement: the catheter will be changed by the treating team as soon as possible and within a maximum of 72 hours from blood culture finalization Central vascular catheter retention: the catheter will not be changed and will be retained until it is no longer needed.
• Cephalosporin VS Carbapenem for low risk AmpC organisms
Cephalosporin (ceftriaxone) at standard doses Carbapenem (like Meropenem, Ertapenem etc) at standard doses
• Routine follow-up blood culture VS No routine follow-up blood culture
Routine follow-up blood culture: routine repeat blood collection 4 days from the index blood collection with positive bacteria. No follow-up blood culture: no routine repeat blood collection 4 days from the index blood collection with positive bacteria

Locations

Country	Name	City	State
Canada	Foothills Hospital	Calgary	Alberta
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	Eastern Regional Health Authority	Saint John's	Newfoundland and Labrador
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Michael Garron Hospital	Toronto	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	North York General Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Sunnybrook Health Sciences Centre	Canadian Institutes of Health Research (CIHR)

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recruitment rate (co-primary outcomes of BALANCE+ vanguard phase)	Recruitment rate will be measured as the number of patients randomized to each study domain, overall, and by individual participating site. Investigators will target a minimum overall recruitment rate of 1 patient/site/month in the de-escalation domain, beta-lactam versus non-beta-lactam stepdown domain, and FUBC domain; and 0.25 patients/site/month in the line replacement domain.	1 year
Primary	Protocol adherence (co-primary outcomes of BALANCE+ vanguard phase)	Protocol adherence will be calculated differently depending on the domain, but in each case will require adherence to the specific intervention arm and complete follow-up for the primary outcome. Investigators will target =90% adherence in each arm of each domain.	1 year
Primary	De-escalation versus no de-escalation domain	Patient-centered, ordinal Desirability of Outcome Ranking (DOOR) outcome: (dead at 90 days) < (alive at 90 days with reinfection and readmission) < (alive at 90 days with reinfection or readmission) < (alive at 90 days with neither reinfection nor readmission); Tie-breaker within ordinal levels: new antimicrobial resistance (AMR) colonization or infection from routine cultures	90 days
Primary	Oral beta-lactam versus non beta-lactam domain	Ordinal DOOR outcome: (dead at 90 days) < (alive at 90 days with reinfection and readmission) < (alive at 90 days with reinfection or readmission) < (alive at 90 days with neither reinfection nor readmission); Tie-breaker within ordinal levels: new AMR colonization or infection from routine cultures	90 days
Primary	Central vascular catheter retention versus replacement domain	Ordinal DOOR outcome: (dead at 90 days) < (alive at 90 days with reinfection and readmission) < (alive at 90 days with reinfection or readmission) < (alive at 90 days with neither reinfection nor readmission); No tie-breaker	90 days
Primary	Low-risk AmpC domain	Ordinal DOOR outcome: (dead at 90 days) < (alive at 90 days with reinfection and readmission) < (alive at 90 days with reinfection or readmission) < (alive at 90 days with neither reinfection nor readmission); Tie-breaker within ordinal levels: new AMR colonization or infection from routine cultures	90 days
Primary	Follow-up blood culture domain	Ordinal DOOR outcome: (dead at 90 days) < (alive at 90 days with reinfection and readmission) < (alive at 90 days with reinfection or readmission) < (alive at 90 days with neither reinfection nor readmission); No tie-breaker	90 days
Secondary	90-day mortality		90 days
Secondary	90-day reinfection		90 days
Secondary	90-day all cause readmission		90 days
Secondary	90-day AMR colonization/infection		90 days
Secondary	90-day Clostridioides difficile infection (CDI)		90 days
Secondary	30-day mortality		30 days
Secondary	60-day mortality		60 days