A phase 2 randomised clinical trial to evaluate the efficacy of anakinra in patients with the acute respiratory distress syndrome (AnakARDS)

Research question: In patients with acute respiratory distress syndrome (ARDS) does treatment with anakinra in addition to usual care, compared with usual care alone, reduce organ dysfunction? Background: ARDS is a common clinical syndrome in the intensive care unit (ICU) and has a 40% mortality rate. Patients with ARDS frequently develop multiple organ failure. There are no pharmacological treatments for ARDS. Interleukin (IL)-1ß is strongly upregulated in the alveolar space and it has broad downstream proinflammatory effects, many of which are implicated in the pathogenesis of ARDS. Blocking this pathway of inflammation offers potential to reduce illness severity and improve outcomes from ARDS. Anakinra is a recombinant IL-1 receptor antagonist that was found to reduce mortality in patients with COVID-19 who had high baseline plasma soluble urokinase plasminogen activator receptor (suPAR). COVID-19 and ARDS have many biological and clinical similarities, and in patients with ARDS high baseline plasma suPAR is associated with increased systemic organ dysfunction and mortality. However, the efficacy of anakinra in patients with ARDS, and whether there is a subgroup of patients identified by baseline plasma suPAR that have greater treatment benefit, is unknown. Overall aim: To evaluate the efficacy of anakinra as a novel therapeutic for patients with ARDS within a phase 2 clinical trial. Specific objectives: 1. To determine the efficacy of treatment with anakinra in reducing organ dysfunction for patients with ARDS. 2. To evaluate how anakinra modulates inflammatory cellular populations, cytokine pathways and inflammasome activity in ARDS. 3. To identify if there are a prospectively identified subgroup of patients with high plasma suPAR who have a greater treatment response to anakinra. Methods: We will conduct a phase 2, multi-centre, randomised, allocation concealed, controlled, open label clinical trial in patients with ARDS. Setting: 7 research-active UK ICUs. Population: Adults within 48-hours of meeting ARDS criteria. Intervention: Anakinra (200mg, intravenous, 8-hourly) for up to 10 days. Comparator: Usual care. Primary outcome: SOFA score at 72 hours following randomisation. Secondary outcomes: 1. SOFA score at days 7, 10, 14 and 28 whilst in the ICU 2. 28-day respiratory support-free days 3. Receipt of new renal replacement therapy within 28 days 4. All-cause mortality at 28 and 90 days 5. ICU and hospital duration of admission and mortality 6. Serious adverse events Mechanistic evaluation: Blood and urine samples will be obtained at baseline, days 3 and 10. Mechanistic outcomes are focussed on evaluating how disruption of IL-1 receptor signalling with anakinra reduces downstream inflammation in ARDS. Feasibility of a future enrichment strategy: Following trial completion, a subsequent analysis that stratifies patients using baseline plasma suPAR will be performed. Sample size: 132 patients, providing 90% power to detect a 2-point difference in SOFA score at 72 hours. Timelines for delivery: Months 1-12 setup and approvals; Months 13-48 trial recruitment and follow-up; Months 49-60 statistical and lab analyses, results dissemination. Anticipated impact and dissemination: This proposal will deliver a phase 2 clinical trial that aims to demonstrate efficacy of anakinra as a therapeutic for ARDS. With continued input from our PPI contributors, we will ensure our findings are widely disseminated to maximise impact.