A Platform Trial for Gram Negative Bloodstream Infections
NCT Number: NCT06537609
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Gram-negative Bacteremia
Interventions: 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
Sponsor: Sunnybrook Health Sciences Centre
Collaborators: Canadian Institutes of Health Research (CIHR)
Sex: ALL
Age: CHILD, ADULT, OLDER_ADULT
Enrollment: 2500
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-04-24
Completion Date: 2028-04
Locations: Foothills Hospital, Calgary, Alberta, Canada|Eastern Regional Health Authority, Saint John's, Newfoundland and Labrador, Canada|The Ottawa Hospital, Ottawa, Ontario, Canada|Niagara Health System, St. Catharines, Ontario, Canada|Sunnybrook Health Sciences Centre, Toronto, Ontario, M4N3M5, Canada|Michael Garron Hospital, Toronto, Ontario, Canada|Mount Sinai Hospital, Toronto, Ontario, Canada|University Health Network, Toronto, Ontario, Canada|Université de Sherbrooke, Sherbrooke, Quebec, Canada

Summary:
BALANCE+ is a perpetual multiple domain randomized controlled platform trial to evaluate various treatment strategies for Gram-negative bloodstream infections (GN BSIs). Each domain addresses critical questions in the management of GN BSIs, aiming to refine treatment strategies, enhance patient outcomes, and reduce antimicrobial resistance.

The initial vanguard pilot RCT (NCT05893147) started on 29 August 2023 and has successfully completed the pilot phase on 24-Apr-2024. All patients enrolled in the vanguard phase are part of the main platform trial.

Primary Outcome Measures: Desirability of Outcome Ranking (DOOR) Ordinal Scale which incorporates death, reinfection, readmission, and for some domains incorporates a tie-breaker of new antimicrobial resistance (AMR)., The primary outcome for each domain will use a Desirability of Outcome Ranking (DOOR) ordinal scale in which patients are categorized into the following mutually exclusive categories, ranked from best to worst status:

1. Alive with no reinfection or readmission.
2. Alive with reinfection OR readmission.
3. Alive with reinfection AND readmission.
4. Dead

For the 3 antibiotic-related domains (the de-escalation versus no de-escalation domain, the beta-lactam versus non-beta-lactam domain, and the low risk AmpC domain) there will be an additional tie-breaker within ordinal levels 1, 2 and 3 based on whether there was new detection of antimicrobial resistance (AMR)., 90 days
Secondary Outcome Measures: 90-day mortality, 90 days|90-day re-infection, 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|Additional Secondary Outcomes for Individual Domains, (i) De-escalation versus no de-escalation

* change in total microbiome diversity between the day of randomization and discharge (or day 30 if earlier)
* net change in resistome AMR burden between the day of randomization and discharge (or day 30 if earlier).

(ii) Beta-lactam versus non-beta-lactam

* antibiotic-related allergic reaction
* antibiotic-related adverse event

(iii) Central vascular catheter replacement versus retention

* pneumothorax or thoracotomy tube insertion related to vascular catheter
* clinically important bleeding
* line associated thrombus
* persistent bacteremia \>5d from initial index culture
* secondary bloodstream infection with new bacterial or fungal organism

(iv) Low-risk AmpC

* isolation of ESBL producing organism or third generation cephalosporin resistant Gram negative organism
* isolation of a carbapenem-resistant organism

  (v) Follow up blood culture domain
* total duration of antibiotic therapy
* hospital length of stay, 90 days