Failure to rescue the trial: lessons from a randomised antibiotic treatment trial in the acute care setting

Background A cluster-randomized cross-over trial assessing whether cephalosporin monotherapy is non-inferior to cefuroxime plus short-course aminoglycoside combination therapy for empirical sepsis treatment was terminated early due to operational futility due to low enrolment and low protocol adherence. We evaluated barriers to enrolment and treatment compliance. Methods Trial enrolment was between May 2022 and May 2023. This mixed-methods study included questionnaires to local research teams (LRTs) and local clinical staff between January and March 2024 addressing barriers to enrolment and prescribing randomized treatment, a scrutiny of screening logs for non-enrolment reasons, and analysis of patient characteristics associated with non-compliance. Individuals working as LRT members and clinicians received questions for both roles, with their role clearly indicated per question. Results In total, 65 questionnaires were completed: 23 by LRT members and 54 by clinical staff (including 12 LRT members). For enrolment, screening of the inclusion and exclusion criteria was considered challenging in one hospital. According to the screening logs, 52.2% of patients were excluded due to at least one exclusion criterion, and 15.6% of eligible patients declined consent for study participation. Primary barriers to prescribe combination therapy were concerns about potential side effects and limited perceived benefit compared to monotherapy. Secondary barriers included supervisors recommending deviations from the study protocol. Difficulty keeping clinical staff informed and trained was reported as relevant barrier for implementation by LRTs, but considered of low importance by the clinical staff. No barriers were reported for monotherapy. Conclusions The main barrier for enrolment was the higher than expected number of patients with an exclusion criterion. The main barrier for treatment compliance was concerns about potential side effects of combination therapy. We recommend quantitative and qualitative pilot studies to identify barriers during the trial design phase, to optimize recruitment strategies and protocol adherence. Trial registration European Union Clinical Trials Register, EUCTR2021-001840-83-NL. Registered on 7 July 2021, https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2021-001840-83