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 thus 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 analyst-blinded 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 (SAEs), serious adverse reactions (SARs), days alive at day 90 without life support, days alive and out of the hospital at day 90 and mortality, health-related quality of life (HRQoL), 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 (ITT) population. DISCUSSION: The CLASSIC trial results will provide important evidence to guide clinicians' choice regarding the IV fluid therapy in adults with septic shock.

Centre for Research in Intensive Care Copenhagen Denmark

Copenhagen Academy for Medical Education and Simulation Rigshospitalet Copenhagen Denmark

Copenhagen Trial Unit Centre for Clinical Intervention Research Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Anaesthesia and Intensive Care Aalborg University Hospital Aalborg Denmark

Department of Anaesthesia and Intensive Care Copenhagen University Hospital Bispebjerg Copenhagen Denmark

Department of Anaesthesia and Intensive Care Herning Hospital Herning Denmark

Department of Anaesthesia and Intensive Care Lillebaelt Hospital Kolding Denmark

Department of Anaesthesia and Intensive Care Nordsjaellands Hospital University Hospital of Copenhagen Hillerød Denmark

Department of Anaesthesia and Intensive Care Randers Hospital Randers Denmark

Department of Anaesthesia and Intensive Care Viborg Hospital Viborg Denmark

Department of Anaesthesia and Intensive Care Zealand University Hospital Køge Denmark

Department of Anaesthesia and Intensive Care Zealand University Hospital Roskilde Denmark

Department of Anaesthesiology Division of Emergencies and Critical Care Rikshospitalet Oslo University Hospital Oslo Norway

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of Clinical Science and Education Section of Anaesthesia and Intensive Care Karolinska Institutet Södersjukhuset Stockholm Sweden

Department of Intensive Care Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Intensive Care Guy's and St Thomas' Hospital London UK

Department of Intensive Care Hospital Vall d'Hebron Barcelona Spain

Department of Intensive Care Medicine Humanitas Research Hospital Milan Italy

Department of Intensive Care Medicine University Hospital Bern University of Bern Bern Switzerland

Department of Intensive Care Medicine University Hospital Brussels Jette Belgium

Department of Intensive Care University Medical Centre Groningen Groningen The Netherlands

Department of Perioperative Medicine and Intensive Care Karolinska University Hospital Huddinge Stockholm Sweden

Department of Public Health Section of Biostatistics University of Copenhagen Copenhagen Denmark

Division of Intensive Care Medicine Department of Anaesthesiology Intensive Care and Pain Medicine University of Helsinki and Helsinki University Hospital Helsinki Finland

Faculty of Medicine and Pharmacy Vrije Universiteit Brussel Brussels Belgium

Intensive Care National Audit and Research Centre London UK

Medical Intensive Care Unit Interni klinika Fakultni Nemocnice Plzen Czech Republic

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Effects of restrictive fluid therapy on the time to resolution of hyperlactatemia in ICU patients with septic shock. A secondary post hoc analysis of the CLASSIC randomized trial

Long-term effects of restriction of intravenous fluid in adult ICU patients with septic shock