BALANCE+ Vanguard Phase

Study Overview
=================
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.

Official Title
-----------------
BALANCE+: A Platform Trial for Gram Negative Bloodstream Infections

Conditions
-----------------
Gram-negative Bacteremia

Intervention / Treatment
-----------------
* 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


Participation Criteria
=================
Eligibility Criteria
-----------------
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 1. 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 i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. 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 i. resistance ii. allergies iii. medical contraindications iv. drug-interaction risk v. other relevant reason 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 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 1. 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)
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |