Treatment of Persistent COVID-19 Smell Dysfunction with Olfactory Training, Co-Ultramicronized Palmitoylethanolamide with Luteolin, or Combined Therapy:  Results of Double-Blinded Multicenter Clinical Trial

Background: Few evidence-based therapies are available for persistent olfactory dysfunction after COVID-19; but recent studies suggest that co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) might promote recovery of smell when combined with olfactory therapy. The proposed mechanism involves regenerating olfactory pathways while counteracting neuroinflammation. The efficacy of um-PEA-LUT alone and at different dosing schedules is unknown. This randomised trial compared the gold standard of combined therapy to monotherapy (olfactory training alone or um-PEA-LUT alone) to assess outcomes of smell recovery in patients with persistent COVID-19 smell impairment.  Methods: In this multicenter, blinded clinical trial, 202 patients with persistent COVID-19 olfactory dysfunction of >6 months duration were randomized to four groups: (1) olfactory training and placebo (control); (2) olfactory training with once daily um-PEA-LUT; (3) once daily um-PEA-LUT alone; and (4) twice daily um-PEA-LUT alone. Study participants underwent a baseline nasal endoscopy followed by olfactory testing (Sniffin’ Sticks odor identification test) at baseline and at 1, 2, and 3 months after initiation of the trial. Recovery of over 3 points were considered significant. Statistical analyses included one-way ANOVA for numeric data and chi-square for nominal data.  Findings: Patients in all groups receiving um-PEA-LUT demonstrated improved rates of olfactory recovery when compared to the placebo control patients; however, the extent of recovery was usually modest without combination therapy. At 90-days, 89.2% in the combined therapy group improved odor identification scores by >3 points, compared to only 38.8% of individuals receiving olfactory training with placebo, 40% receiving twice daily um-PEA-LUT, and 41.6% receiving once daily um-PEA-LUT.  Interpretation: Olfactory training plus once daily um-PEA-LUT improved olfactory recovery compared to either therapy alone. Further investigations are necessary to determine longer term outcomes. Trial Registration: This study was registered at Clinicaltrials.gov in April 2021 with number: 20112020PGFN Funding: There was no funding source for this study Declaration of Interest: We declare no competing interests Ethical Approval: The study was authorized by the Institutional Review Board of Humanitas University (identifier 3002),