Background Due to its antioxidative, anti-inflammatory, anti-apoptosis, and antifatigue properties, molecular hydrogen (H2) is potentially a novel therapeutic gas for acute coronavirus disease 2019 (COVID-19) patients. Aim To determine the efficacy and safety profile of hydrogen rich water (HRW) to reduce the risk of progression of COVID-19. Design and settings We conducted a phase 3, triple-blind, randomized, placebo-controlled trial to evaluate treatment with HRW started within 5 days after the onset of signs or symptoms in primary care patients with mild-to-moderate, laboratory-confirmed COVID-19 and at least one risk factor for severe COVID-19 illness. Method Participants were randomly assigned to receive HRW or placebo twice daily for 21 days. The composite primary endpoint was the incidence of clinical worsening (dyspnea, fatigue) associated with a need for oxygen therapy, hospitalization or death at day-14; the incidence of adverse events was the primary safety end point. Results A total of 675 participants were followed up until day-30. 337 in the HRW group and 338 in the placebo group. Baseline characteristics were similar in the two groups. HRW was not superior to placebo in preventing clinical worsening at day-14: in H2 group, 46.1% met a clinical deterioration, 43.5% in the placebo group, Hazard Ratio 1.09, 90% confidence interval [0.90-1.31]. One death was reported in the H2 group and 2 in the placebo group at day-30. Adverse events were reported in 91 (27%) and 89 (26.2%) participants respectively. Conclusion Twice-daily ingestion of HRW from the onset of COVID-19 symptoms for 21 days did not reduce clinical worsening. Keywords: COVID-19; Molecular Hydrogen; Administration, Oral; Primary health care; Outcome Assessment;

The authors have declared no competing interest.

NCT04716985

The HydroCovid study was supported by Drink HRW, TIMC, University Grenoble-Alpes Foundation, Agiradom Association, AG2R, AGdermi association

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Approved by the French Agency for the safety of Drugs and Health Products, the Sud Mediterrannée II Committee for the protection of persons (reference 2020 A03137 32) and was compliant with General Data Protection Regulation

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