Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent β-lactam antibiotic infusion in critically ill patients with sepsis

Abstract

BACKGROUND: The β-Lactam Infusion Group (BLING) III study is a prospective, multicentre, open, phase 3 randomised controlled trial comparing continuous infusion with intermittent infusion of β-lactam antibiotics in 7000 critically ill patients with sepsis. OBJECTIVE: To describe a statistical analysis plan for the BLING III study. METHODS: The statistical analysis plan was designed by the trial statistician and chief investigators and approved by the BLING III management committee before the completion of data collection. Statistical analyses for primary, secondary and tertiary outcomes and planned subgroup analyses are described in detail. Interim analysis by the Data Safety and Monitoring Committee (DSMC) has been conducted in accordance with a pre-specified DSMC charter. RESULTS AND CONCLUSIONS: The statistical analysis plan for the BLING III study is published before completion of data collection and unblinding to minimise analysis bias and facilitate public access and transparent analysis and reporting of study findings. TRIAL REGISTRATION: ClinicalTrials.gov Registry NCT03212990.

Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis

“…The study protocol (Supplement 1) and statistical analysis plan (Supplement 2) have been published previously. 19,20 The trial was approved by the relevant human research ethics committee or equivalent in each region; institutional approval was obtained as per site requirements. In some jurisdictions, approval was obtained for enrollment prior to consent in certain circumstances (eMethods in Supplement 3); in all countries, written informed consent was obtained from patients or their legal surrogate with documented verbal consent obtained in some regions during the SARS-CoV-2 (COVID-19) pandemic as per ethics committee approval (eMethods in Supplement 3).…”

Fred J Boyd Oration 2021

“…It is no longer double-blind or double dummy because of the nature of the primary endpoint. 10,11 We have now recruited >7000 patients in >100 ICUs in three continents and by the middle of next year should have results which will change global practice one way or another. This research program highlights that nurturing small things allows them to become big things, and the team of Jeff Lipman and myself has grown into a much bigger team which includes local key figures, like Joel Dulhunty, Os Cotta, John Myburgh, and Dorrilyn Rajbhandari.…”

“…BLING 3 is evaluating 90‐day mortality rates between sepsis patients randomised to continuous or short infusions of meropenem or piperacillin/tazobactam. It is no longer double‐blind or double dummy because of the nature of the primary endpoint 10,11 . We have now recruited >7000 patients in >100 ICUs in three continents and by the middle of next year should have results which will change global practice one way or another.…”

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“…In this issue, we present both the TEAM trial 11 and BLING III trial protocols. 12 Assessment of quality of care and performance and safety are also part of the intensive care community 13 and are highlighted by articles on hospital-acquired complications of critical illness, 14 interhospital transport of sick children, 15 and assessment of ICU activity and strain. 16 Coronavirus disease 2019 (COVID-19) has been a dominant topic in the pages of CCR since the onset of the pandemic.…”