Conservative vs liberal fluid therapy in septic shock (CLASSIC) trial—Protocol and statistical analysis plan

Abstract

Introduction Intravenous (IV) fluid is a key intervention in the management of septic shock. The benefits and harms of lower versus higher fluid volumes are unknown and clinical equipoise exists. We describe the protocol and detailed statistical analysis plan for the Conservative versus Liberal Approach to fluid therapy of Septic Shock in the Intensive Care (CLASSIC) trial. The aim of the CLASSIC trial is to assess benefits and harms of IV fluid restriction versus standard care in adult intensive care unit (ICU) patients with septic shock. Methods CLASSIC trial is an investigator-initiated, international, randomised, stratified, and analystblinded trial. We will allocate 1554 adult patients with septic shock, who are planned to be or are admitted to an ICU, to IV fluid restriction versus standard care. The primary outcome is mortality at day 90. Secondary outcomes are serious adverse events, serious adverse reactions, days alive at day 90 without life support, days alive and out of hospital at day 90, and mortality, health-related quality of life, and cognitive function at 1 year. We will conduct the statistical analyses according to a pre-defined statistical analysis plan, including three interim analyses. For the primary analysis we will use logistic regression adjusted for the stratification variables comparing the two interventions in the intention-to-treat population. Discussion The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding IV fluid therapy in adults with septic shock.

Long‐term patient‐important outcomes after septic shock: A protocol for 1‐year follow‐up of the CLASSIC trial

“…CLASSIC is an ongoing investigator‐initiated, international, parallel‐grouped, randomised 1:1 by a computer‐generated allocation sequence list, stratified, analyst‐blinded trial (NCT03668236). In the CLASSIC trial, we assess the benefits and harms of restricted vs standard‐care IV fluid therapy in adult ICU patients with septic shock, stratified for haematological or metastatic cancer (yes/no) and trial site . The protocol and statistical analysis plan (SAP) for the 90‐day follow‐up have been published .…”

“…In the CLASSIC trial, we assess the benefits and harms of restricted vs standard‐care IV fluid therapy in adult ICU patients with septic shock, stratified for haematological or metastatic cancer (yes/no) and trial site . The protocol and statistical analysis plan (SAP) for the 90‐day follow‐up have been published . The planned sample size is 1554 patients.…”

“…We will provide 99% confidence intervals (CI) between means (if data are nearly normally distributed) or otherwise between medians (by bootstrapping). We will present the results as adjusted absolute and relative risk differences, computed using GLMs with appropriate link functions and binomial error distribution, using 99% CIs for the secondary outcomes ( P ‐value .01) due to the multiplicity of these as stated in the CLASSIC protocol …”

“…Intravenous (IV) fluid therapy is a recommend key intervention in septic shock; however, the evidence on how to manage fluids in these intensive care unit (ICU) setting is of low quality . Therefore, the ongoing multi‐centre, randomised clinical trial (RCT) ‘The Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care’ (CLASSIC) assesses the benefits and harms of IV fluid restriction vs standard‐care in adult ICU patients with septic shock …”

“…There are at least two ongoing restricted vs standard IV fluid trials in patients with sepsis/septic shock; the Crystalloid Liberal Or Vasopressor Early Resuscitation in Sepsis (CLOVERS) trial follows patients until day 90 with in‐hospital mortality as primary outcome, and the CLASSIC trial follows patients until 1 year, assessing mortality, HRQoL and cognitive function . The CLASSIC trial seems to be the only trial measuring long‐term patient‐important outcomes …”