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

A cluster-randomised cross-over trial assessing whether cephalosporin monotherapy is non-inferior to cefuroxime plus short-course aminoglycoside combination therapy for empirical sepsis treatment was terminated for operational futility due to low enrolment and low protocol adherence. We evaluated barriers to enrolment and treatment compliance.

Trial enrolment was between May 2022 and May 2023. For this mixed-methods study, we used questionnaires to identify barriers to enrolment and prescribing randomised treatment among local research teams (LRTs) and local clinical staff, which were obtained between January and March 2024. In addition, we investigated screening logs for non-enrolment reasons and determined patient characteristics associated with non-compliance. Clinicians being part of LRT received questionnaires for both roles, with their role clearly indicated per question.

In total, 65 questionnaires were completed: 23 by LRT members and 54 by clinical staff (including 12 LRT members). For patient enrolment, screening of inclusion and exclusion criteria was considered challenging in one hospital. According to 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 study protocol. Keeping clinical staff informed and trained during the study was reported as relevant barrier for implementation by LRTs, but considered of low importance by clinical staff. No barriers were reported for monotherapy.

In this study, the main barrier for patient enrolment was the higher than expected proportion of patients with exclusion criteria. 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 optimise recruitment strategies and protocol adherence.

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.