BALANCE+ Vanguard Phase

Sponsor

Sunnybrook Health Sciences Centre (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05893147

Collaborator

Canadian Institutes of Health Research (CIHR) (Other)

Enrollment

Arms

49.9

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Gram-negative Bacteremia	Other: De-escalation VS No De-escalation Other: Oral beta-lactams VS non beta-lactams Other: Central vascular catheter retention VS Central vascular catheter replacement Other: Cephalosporin VS Carbapenem for low risk AmpC organisms Other: Routine follow-up blood culture VS No routine follow-up blood culture	N/A

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

72 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Jun 30, 2027

Anticipated Study Completion Date :

Jul 30, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: De-escalation VS No De-escalation	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.
Active Comparator: Oral beta-lactams VS Oral Non-beta-lactams	Other: 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.
Active Comparator: Central vascular catheter retention VS Central vascular catheter replacement	Other: 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.
Active Comparator: Cephalosporin VS Carbapenem for low risk AmpC organisms	Other: Cephalosporin VS Carbapenem for low risk AmpC organisms Cephalosporin (ceftriaxone) at standard doses Carbapenem (like Meropenem, Ertapenem etc) at standard doses
Active Comparator: Routine follow-up blood culture VS No routine follow-up blood culture	Other: 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

Outcome Measures

Primary Outcome Measures

Recruitment rate (co-primary outcomes of BALANCE+ vanguard phase) [1 year]
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.
Protocol adherence (co-primary outcomes of BALANCE+ vanguard phase) [1 year]
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.
De-escalation versus no de-escalation domain [90 days]
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
Oral beta-lactam versus non beta-lactam domain [90 days]
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
Central vascular catheter retention versus replacement domain [90 days]
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
Low-risk AmpC domain [90 days]
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
Follow-up blood culture domain [90 days]
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

Secondary Outcome Measures

90-day mortality [90 days]
90-day reinfection [90 days]
90-day all cause readmission [90 days]
90-day AMR colonization/infection [90 days]
90-day Clostridioides difficile infection (CDI) [90 days]
30-day mortality [30 days]
60-day mortality [60 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

PLATFORM INCLUSION CRITERIA

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

PLATFORM EXCLUSION CRITERIA

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

DOMAIN SPECIFIC INCLUSION AND EXCLUSION CRITERIA

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

Inclusion Criteria

included in BALANCE+ platform

Exclusion Criteria

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

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

patients with a suspected or proven polymicrobial source of infection

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

Inclusion Criteria

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

Exclusion Criteria

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

no-de-escalation arm

no non-beta-lactam options due to any or all of

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

no beta-lactam options due to any or all of

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

Inclusion Criteria

included in BALANCE+ platform
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

patient has no ongoing need for a central vascular catheter
patient has definite indication for central vascular catheter removal
ongoing septic shock with definite/probable line source
concomitant S. aureus bacteremia
concomitant candidemia
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)
definite alternative source of GN BSI

(D) LOW-RISK AmpC DOMAIN

Inclusion Criteria

included in BALANCE+ platform
positive blood culture with GN bacterium, of the following species
Serratia spp.
Morganella spp.
Providencia spp.
Proteus spp. other than P.mirabilis
organism is sensitive to ceftriaxone

Exclusion Criteria

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

(E) FOLLOW UP BLOOD CULTURE DOMAIN

Inclusion Criteria

included in BALANCE+ platform

Exclusion Criteria

patient already discharged home prior to day 4
definite indication for repeat blood culture testing
concomitant Staph. aureus bacteremia
concomitant Candidemia
clinical suspicion for infective endocarditis (e.g., presence of prosthetic valve, implantable cardiac device)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Sunnybrook Health Sciences Centre
Canadian Institutes of Health Research (CIHR)

Investigators

Principal Investigator: Nick Daneman, MD, Sunnybrook Health Sciences Centre
Principal Investigator: Rob Fowler, MD, Sunnybrook Health Sciences Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Sunnybrook Health Sciences Centre

ClinicalTrials.gov Identifier:

NCT05893147

Other Study ID Numbers:

4369

First Posted:

Jun 7, 2023

Last Update Posted:

Jun 7, 2023

Last Verified:

May 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Study Results

No Results Posted as of Jun 7, 2023