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Background
Approximately one in four critically ill patients who receive enteral nutrition (EN) in the intensive care unit (ICU) does not survive to hospital discharge [1]. For those that do survive, rapid and substantial muscle wasting occurs [2, 3], which is strongly associated with adverse patient-centered outcomes [4, 5–6]. International critical care nutrition guidelines recommend protein delivery of at least 1.2 g/kg body weight/day [7, 8]. Critically ill patients typically receive dietary protein at rates < 1.0 g/kg body weight/day [9, 10] and it has been proposed that augmenting dietary protein in critical illness could improve outcomes [11, 12]. However, it is unclear from existing data whether augmenting dietary protein in the ICU improves patient outcomes, with existing meta-analysis indicating that increased protein could reduce mortality by up to 12% or increasing mortality by up to 11% [13, 14].
The TARGET Protein trial is a cluster randomized, cross-sectional, double cross-over, registry-embedded, pragmatic open-label clinical trial with the aim of evaluating the effect of higher enteral protein delivery (augmented protein) on clinical outcomes of critically ill adult patients when compared to usual care [15]. This manuscript describes the statistical analysis plan for the TARGET Protein trial and supersedes the plan provided in the previously published protocol [15] and trial registration (Australian New Zealand Clinical Trials Registry, ACTRN12621001484831).
At least three relevant clinical trials have emerged since the commencement of the TARGET Protein trial. During the recruitment for the TARGET Protein trial, the EFFORT Protein trial was published (25 January 2023) [16]. That trial evaluated the effect of increased protein (≥ 2.2 g/kg/day) compared to usual care (protein ≤ 1.2 g/kg/day) and was ceased with less than one third of the planned cohort recruited at 1301 patients due to slow recruitment consequent upon the COVID-19 pandemic. The revised primary outcome of the EFFORT Protein trial was “time to discharge alive from hospital up to 60 days after ICU admission” and there was no evidence of a between group difference [16]. The authors reported potentially worse outcomes in the sub-group of patients with acute kidney injury [17] and high SOFA score (≥ 9) on admission; however, the authors acknowledged multiplicity of testing with accompanying inflation of type 1 errors. Further, the sub-group with acute kidney injury was defined according to the Kidney Disease: Improving...