INtravenous Iron and eryThropoietin to treat Anaemia following CriTical care-2 (INTACT-2): A multi-centre, randomised, parallel group, double blind, placebo controlled, clinical efficacy trial

RESEARCH QUESTION: What is the clinical efficacy and cost-effectiveness of intravenous (IV) iron and recombinant human erythropoietin (rHuEPO) vs. placebo for treating anaemia (haemoglobin (Hb) =100 g/L) post critical illness? BACKGROUND: Nearly 100,000 patients are discharged from intensive care (ICU) with moderate-severe anaemia (Hb =100 g/L) each year in the UK. We have shown that anaemia in ICU survivors is associated with poor health outcomes, including prolonged hospitalisation, more hospital readmissions, increased mortality, and poor health-related quality of life (HRQoL). Identifying modifiable risk factors and treatments for improving recovery from critical illness are research priorities of the James Lind Alliance, NICE and NIHR. IV iron and rHuEPO are biologically plausible treatments for the anaemia of inflammation that accompanies critical illness, particularly if given at ICU discharge and once organ failure has resolved. Our systematic reviews and completed feasibility trials indicate that IV iron and rHuEPO have acceptable safety, but high-quality clinical efficacy data are lacking. Our clinician survey in December 2021 (40 UK ICUs) indicated practice variation,clinical uncertainty and no accepted standard of care. The Intensive Care Society (June 2022) listed INTACT-2 as a UK ICU research priority. PRIMARY OBJECTIVE: To determine the clinical efficacy of IV iron and rHuEPO for treatment of anaemia in ICU survivors. The primary outcome is physical function, assessed by the Physical Component Summary (PCS) of the Medical Outcomes Study SF-36 HRQoL questionnaire at 90 days post-randomisation (PCS-90). STUDY DESIGN: A multicentre (25 UK ICUs) double-blind, placebo controlled RCT of IV iron (1g ferric carboxymaltose) and rHuEPO (darbepoetin 1.5 mcg/kg) versus placebo, administered within 48 hours of ICU discharge. The study is powered to detect a difference of 5 points in PCS-90 with a sample size of 508 patients. Moderation analyses will explore prespecified baseline factors that may be associated with efficacy. Mediation analyses will explore the relative contributions of anaemia treatment (assessed by measuring Hb) and inflammation suppression (assessed by measuring C-reactive protein) on outcomes. We will undertake a within-trial health economic evaluation (HEE) at 90 days. TIMELINES: INTACT-2 will last 40 months. ANTICIPATED IMPACT AND DISSEMINATION: INTACT-2 will provide efficacy and cost-effectiveness data on the use of IV iron and rHuEPO for treating anaemia in ICU survivors. Moderation analyses will explore which patients gain the most clinical benefit to inform future precision medicine approaches. Mediation analyses will provide confirmatory data on the two key biological pathways through which we hypothesise the interventions are acting on. The use of a HRQoL primary outcome measure, and the inclusion of a full HEE, will allow seamless progression from efficacy to effectiveness and shorten the time to clinical implementation if benefit is demonstrated. Conversely, lack of efficacy will provide evidence for disinvestment and avoidance of treatment over-burden. Results will be published in peer-reviewed journals and presented at national and international conferences. Our results will inform clinical guideline groups (with whom we are already working) to translate findings into practice. We will work with our PPI members to provide trial participants with summary results in a range of accessible formats.