Efficacy of antioxidant therapy in mild to moderate SARS-CoV-2 infection: A pilot experimental arm of the CanTreatCOVID adaptive platform trial

Background: Although the acute phase of the COVID-19 pandemic has passed, SARS-CoV-2 continues to cause outpatient morbidity. Antioxidant micronutrients support immune regulation and may offer a low-cost, scalable adjunctive treatment in early infection. Objective: To evaluate a pilot combination antioxidant therapy within CanTreatCOVID. Methods: This pilot sub-protocol enrolled non-hospitalized adults across five Canadian provinces (September 5th, 2024-March 31st, 2025) with mild-to-moderate SARS-CoV-2 infection within five days of symptom onset. Participants were randomized to usual care plus a 10-day antioxidant regimen (selenium 300 g, zinc 40 mg, lycopene 45 mg, vitamin C 1.5 g) or usual care alone. Pilot objectives assessed feasibility, retention, adherence, and safety. The primary outcome was hospitalization or death within 28 days; exploratory outcomes included recovery and symptom measures by day 14. Results: Eighty-one participants were randomized (41 antioxidant; 40 usual care). Retention was high 85.4% antioxidant; 82.5% usual care), and 90.2% of antioxidant participants completed the intervention course. Adverse events were infrequent (9.8% vs 2.5%), with no serious adverse events reported. No deaths occurred in either group; no hospitalizations occurred in the antioxidant arm versus 2/40 (5%) in usual care. By day 14, recovery was reported in 32/40 (80.0%) participants receiving antioxidants versus 23/36 (63.9%) in usual care (OR 2.128; 95% CI 0.7474.871). Sustained alleviation of all symptoms occurred in 38/40 (95.0%) versus 29/36 (80.6%), respectively (OR 3.498; 95% CI 0.872 --10.017). Return to usual activity by day 14 occurred in 38/40 (95.0%) versus 30/36 (83.3%) (OR 3.113; 95% CI 0.762--9.022). Adjusted between-group differences in dietary intake were not statistically significant. Conclusions: Combination antioxidant therapy was feasible to deliver in a decentralized outpatient setting, with high adherence and tolerability. While the trial was not powered for definitive efficacy conclusions, consistent directional improvements across symptom outcomes support evaluation of this host-directed antioxidant strategy in larger trials. Keywords: Adaptive Platform Trial; Antioxidant Therapy; SARS-CoV-2 ; Outpatient Therapeutics; Micronutrient Supplementation Trial registration number: https://clinicaltrials.gov/study/NCT05614349