IntroductionSulforaphane can induce the transcription factor, Nrf2, promoting anti-oxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were treated with stabilised, synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation.MethodsDouble-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once-daily for 14 days) conducted in Dundee, UK, November 2020–May 2021. Patients had radiologically-confirmed CAP and CURB65 score≥1. The primary outcome was the 7-point WHO clinical status scale at day-15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes.ResultsThe trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. SARS-CoV-2 infection was the cause of CAP in 103(77%) cases.SFX-01 treatment did not improve clinical status at day 15 (adjusted(a)OR 0.87, 95%CI 0.41–1.83,p=0.71), time to clinical improvement (aHR 1.02(0.70–1.49)), length of stay (aHR 0.84(0.56–1.26)), or 28-day mortality (aHR 1.45(0.67–3.16)).The expression of Nrf2 targets and pro-inflammatory genes, including IL6, IL1β and TNFα, was not significantly changed by SFX-01 treatment. At day 8 and 15, respectively, 310 and 42 significant differentially-expressed genes were identified between groups (FDR-adjusted-p<0.05, |Log2FC|>1).ConclusionSFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.