General study design
We conducted a pilot RCT of 7 versus 14 days of antibiotic treatment for patients with bloodstream infection, which was identical to our prior BALANCE-ICU pilot RCT [9, 10], except that it focused on patients admitted to general medical and surgical wards. In this BALANCE-Ward pilot trial, as per the prior BALANCE-ICU pilot trial focused on critically ill patients, randomization was determined through a central, web-based system (http://www.randomize.net) with variable block sizes of four to six patients, stratified by site. The intervention related only to the duration of treatment, with patients randomized 1:1 in parallel to 7 versus 14 days of treatment. All other aspects of care (antibiotic selection, doses, intervals, routes of delivery, and timing of hospital discharge) were at the discretion of the clinical team. Participant and clinician blinding and placebo controls were not used given the diversity of pathogens and underlying foci of infection, but allocation concealment was maintained until the seventh day of treatment to mitigate selection bias and differential treatment. The central study team and statistician were blinded to treatment group. The BALANCE-Ward pilot trial was registered separately on Clinicaltrials.gov (NCT02917551), with unique ethics approval at all participating sites, so that enrolled patients could be kept distinct from the main trial until completion of the pilot and evaluation of feasibility.
The BALANCE-Ward pilot trial was launched at Sunnybrook Health Sciences Centre (SHSC) in October 2016, and then after 1 year extended to five other active BALANCE sites, including The Ottawa Hospital (TOH), Kingston General Hospital (KGH), Hamilton General Hospital (HGH), St. Joseph’s Health Centre (SJHC) Toronto, and North York General Hospital (NYGH).
The inclusion criteria differed, by definition, from the prior BALANCE pilot RCT [9, 10] in that we considered all adult patients with a blood culture reported as positive with a pathogenic bacterium while on a non-ICU ward rather than reported as positive while in an ICU. However, the exclusion criteria were unchanged from the BALANCE pilot RCT: previously enrolled patients, those with neutropenia, organ transplantation, prosthetic valves, endovascular grafts, suspected or documented syndromes requiring prolonged treatment (endocarditis, osteomyelitis, undrained abscess, unremoved prosthetic infection), patients with a single positive culture of a common contaminant organism, or bloodstream infection with Staphylococcus aureus, Staphylococcus lugdunensis, or fungal organisms.
Recruitment and consent
Potentially eligible patients were identified through microbiology laboratory reports of positive blood cultures. The site research coordinator screened the medical records of these patients to confirm that they met all inclusion criteria, and no exclusion criteria, and then provided patients with study information materials. Consenting patients could be enrolled any time up to the seventh day of adequate antibiotic treatment .
Primary feasibility outcomes and secondary clinical outcomes
As per the original BALANCE-ICU pilot RCT, the co-primary feasibility outcomes were (1) recruitment rates and (2) adherence to treatment protocol. Protocol adherence was defined as receipt of 7 ± 2 days of antibiotics or 14 ± 2 days of antibiotics for patients randomized to shorter versus longer duration treatment, respectively. We did not target a specific protocol adherence rate to consider the trial feasible, but sought to determine whether the protocol adherence rate would exceed the rate seen in the BALANCE ICU pilot RCT (77%) . As with the BALANCE ICU pilot RCT, we expected that there would be some patients for whom clinicians would continue antibiotic treatment beyond the assigned duration because of concerns of new infection, persistent infection, or previously unrecognized deep-seated infection. These were counted as protocol deviations. The target recruitment rate was an average of one patient per site per month to consider including ward enrolments in the BALANCE main trial. The panel of secondary clinical outcomes (e.g., length of stay, mortality, antibiotic-free days, Clostridiodes difficile, and antibiotic resistant organisms) were identical to those collected in the original BALANCE pilot RCT [9, 10]. Included among these secondary outcomes was the planned primary outcome from the main BALANCE RCT, 90-day mortality. Antibiotic-free days were calculated as the number of days alive and not on any antibiotics in the time period from collection of the index blood culture to 28 days after this date; patients that died prior to day 28 were assigned 0 antibiotic-free days. Treatment adherence and clinical outcomes were recorded by the site research coordinator, via chart review and discussion with the clinical team if needed.
Data collection and follow-up
Patients were followed throughout the hospital stay to a 90-day maximum, with capture of baseline characteristics and outcome information on the same electronic case report form used for the BALANCE main trial. Ninety-day mortality was collected via follow-up phone call 90 days from the index bacteremia.
There were no interim analyses or stopping rules within this pilot RCT. As with our initial BALANCE pilot RCT, we planned a priori to maintain blinding of treatment assignment in the BALANCE-Ward pilot RCT . A feasibility pilot RCT is not powered to identify clinically important differences in safety or efficacy endpoints, but rather this is the goal of the BALANCE main RCT. We analyzed the BALANCE-Ward pilot RCT results as a single cohort, describing overall rates of recruitment per site per month and overall protocol adherence as the co-primary feasibility outcomes of interest.
Next, we compared these feasibility outcomes to those achieved during our initial BALANCE-ICU pilot RCT . Poisson regression was used to compare recruitment rates per month in the ICU versus non-ICU pilots; chi-square test was used to compare protocol adherence. To further evaluate the difference between the two pilot RCTs we compared baseline patient characteristics, pathogens, foci of infection, and clinical outcomes among ward and ICU patients; the chi-square test or Fischer’s exact test were used to compare categorical variables, while a t-test or the Wilcoxon rank sum test were used to compare continuous variables. The Wilson Score method was used to determine 95% confidence intervals. P values were not adjusted for multiple comparisons.
If the BALANCE-Ward pilot demonstrated feasibility, we planned to consider merging the ward-based protocol with the ICU-based protocol of the BALANCE main trial. Therefore, we estimated the percentage of recruited patients that would be enrolled from ICU versus non-ICU wards as a function of the percentage of sites expanding to hospital-wide enrolments. Next, we estimated the impact on overall trial sample size and non-inferiority margins as a function of the proportion of anticipated ICU versus ward enrolments at the time of trial completion. For these calculations we estimated the 90-day mortality for ward patients using outcome data from this ward pilot RCT, and we estimated the mortality for ICU patients from up-to-date data from the ongoing BALANCE main RCT. At the time the ward pilot was completed, 600 patients had been enrolled and reached the 90-day endpoint in the BALANCE main trial.
Sample size calculation
We sought to enroll a minimum of 115 patients (to equal the sample size of our BALANCE-ICU pilot) , but to improve generalizability of the BALANCE-Ward pilot trial we planned to continue enrolment until successful enrolment of at least one patient at all five additional non-central study sites. Recruitment extended from 17 October 2016 to 12 December 2018.