Efficacy of anakinra in reducing progression to organ dysfunction in patients with pneumonia (INSPIRE): a randomised, double-blind, placebo-controlled, phase IIa trial.

Background: Early recognition of risk of death in pneumonia and start of precision immunotherapy to improve outcomes is an unmet need. We hypothesized that a precision strategy approach combining early recognition of interleukin (IL)-1 activation coupled with Anakinra treatment may improve pneumonia outcome. Methods: INSPIRE is a prospective, double-blind randomized placebo-controlled trial which recruited hospitalized adults with community-acquired or hospital-acquired pneumonia, with qSOFA (quick sequential organ failure assessment) equal to 1 and plasma presepsin (soluble CD14) more than 350 pg/ml. Patients were 1:1 randomised to standard-of-care medication plus either subcutaneous placebo or subcutaneous Anakinra 100 mg once daily for 10 days. The primary endpoint was progression into organ dysfunction defined as meeting at least one of the following two conditions; (i) at least 2-point increase of the baseline SOFA score by day 7 and/or (ii) death by day 90. This was analyzed in the intention-to-treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2022-002390-28) and ClinicalTrials.gov (NCT05785442). Findings: Patients were enrolled between March 2023 and June 2024; 30 patients in the placebo arm and 30 patients in the Anakinra arm were the ITT population. The primary endpoint was met in 50·0% (15 patients) of placebo-treated and in 20·0% (6 patients) of Anakinra-treated patients (difference 30·0% [5·9 to 49%]; p: 0·011). 90-day mortality was 43·3% (13 patients) and 20·0% (6 patients) (difference 23·3% [0 to 43·7%]; p: 0·029). The overall incidence of serious treatment-emergent adverse events (TEAEs) in the placebo group was 50% and in the Anakinra group 33·3%. None of the serious TEAEs was judged to be related to treatment assignment. Production of TNFα and ΙFNγ by blood mononuclear cells was decreased. Interpretation: Presepsin-guided Anakinra treatment prevents progression of pneumonia to organ dysfunction and death. The mechanism of benefit is associated with attenuation of cytokine production. Funding: Hellenic Institute for the Study of Sepsis; PHC Europe BV; Swedish Orphan Biovitrum AB.