PRECISE
REGRESSION, SECONDARY, PCT, ENDOTHELIAL DYSFUNCTION
The aim of the PRECISE sub-study is to identify whether the effectiveness of the PCT-guided algorithm in reducing IV antibiotic duration differs between patients with different endotypes, based on two biomarkers: MR-proADM, a marker of endothelial dysfunction [The PRECISE sub-study will take place at a subset of BATCH sites. Additional blood samples will be taken at randomisation, in both the intervention and the control arm. When extra blood samples are taken for routine care, then serial blood samples will also be taken for the PRECISE biomarkers, but no additional venepuncture or finger pricks will be performed.Outcome definitions will be the same as in the host trial (BATCH). The primary outcome is duration of IV antibiotic treatment, and secondary outcomes are:Total duration of antibiotics (IV and oral)Time to switch from broad spectrum to narrow spectrum antibioticsTime to discharge from hospitalSuspected ADRHAI up to 28 daysSample size calculation for the PRECISE sub-study was based on a comparison between three subgroups, separately for each biomarker: In the sample size calculation for MR-proADM, we assumed median antibiotic durations of 2 versus 4 days (control vs. PCT) in the low MR-proADM subgroup, 7 versus 5 days (control vs. PCT) in the intermediate MR-proADM subgroup, and 10 versus 5 days (control vs. PCT) in the high MR-proADM subgroup. To detect an arm-by-subgroup interaction effect of this size with 90% power whilst controlling the type I error rate at 5%, we need 25 participants per biomarker subgroup in each trial arm [In the primary PRECISE analysis, we will fit a Cox proportional hazards model with duration of IV antibiotic treatment as dependent variable. We will test the interaction between biomarker score and treatment arm, separately for MR-proADM and for ImmunoXpert, using the procedure described for subgroup analyses in the “Subgroup analyses” section.Analysis of the secondary outcomes will involve similar regression models, depending on the type of the outcome variable. In a further secondary analysis with IV antibiotic duration as the outcome, we will test the interaction between treatment arm and biomarker subgroups, categorised according to the following criteria: MR-proADM high (≥ 0.7 nmol/l) or low (< 0.7 nmol/l) [All PRECISE participants will remain in the trial arm assigned by randomisation in the host trial, regardless of protocol deviations or non-adherence, and will be included in all analyses if outcome and biomarker data are available. Missingness within the PRECISE sub-study will be reported for each outcome as described in the “Missing data” section. We will present a descriptive summary of serial biomarker measurements, including the distributions of the observation intervals and of the number of observations per patient.