Abstract: www.nature.com/scientificreports OPEN A prospective, randomized, open‑label trial of early versus late povidone‑iodine gargling in patients with COVID‑19 Akifumi Matsuyama 1*, Hanayuki Okura 1, Shyoji Hashimoto 2 & Toshio Tanaka 3,4 Povidone-iodine (PVP–I) is a broad-spectrum antiseptic reagent that has been used for over 50 years. The purpose of this study is to look into the effect of gargling with PVP–I gargling on virus clearance and saliva infectivity in COVID-19. A prospective, randomized, open-label trial of intervention with PVP–I was conducted at three quarantine facilities in Osaka, Japan, enrolling adolescents and adults with asymptomatic-to-mild COVID-19. Patients were randomly allocated to the early and late intervention group at a 1:1 ratio. The early group gargled with PVP–I from days 2 to day 6; the late group gargled with water first, then with PVP–I from day 5 after sampling till day 6. The primary and secondary endpoints were viral clearance for SARS-CoV-2 using RT-qPCR at days 5 and 6, respectively, and the investigational endpoint was saliva infectivity clearance on day5. We enrolled 430 participants, with 215 assigned to each group, and 139 in the early group and 140 in the late had a positive saliva RT-qPCR test on day 2. On day 5, the early group had a significantly higher RT-qPCR negative rate than that of the late group (p = 0.015), and the early had a significantly higher clearance rate of infectivity (p = 0.025). During the PVP–I intervention, one participant reported oropharyngeal discomfort. Gargling with PVP–I may hasten virus clearance and reduce viral transmission via salivary droplets and aerosols in patients with asymptomatic-to-mild COVID-19. (Clinical trial registration numbers: jRCT1051200078 and dateof registration: 24/11/2020). The salivary SARS-CoV-2 viral load is thought to play a significant role in the accelerated transmission of coronavirus disease 2019 (COVID-19)1. A reduction in salivary viral load is thought to suppress ­transmission2, and some studies have suggested that mouthwash and/or gargling with povidone-iodine (PVP–I) may have an antiseptic effect for SARS-CoV-2, reducing its viral l­ oad3. However, it is unknown whether gargling with PVP–I would eliminate salivary viral load and infectivity in COVID-19 patients in vivo. PVP–I is a polyvinylpyrrolidone (PVP) and iodine complex that has an antiseptic effect by releasing iodine. Its mechanism of action involves the use of iodine to oxidize microbial components. PVP–I has previously been shown to have an antiseptic effect on SARS-CoV and MERS in vitro4,5, and it was also effective against SARSCoV-26. A single in vitro gargle with PVP–I reduced the salivary viral load in two of four patients with a high salivary viral ­load7. Although recent studies have confirmed the short-term effects of reducing salivary viral load in a small number of patients with COVID-19 8, there have been no prospective randomized intervention studies involving PVP–I gargling. The purpose of this study was to see if gargling with PVP–I will reduce viral load and SARS-CoV-2 infectivity in patients with COVID-19. Materials and methods Study design. This was a prospective, randomized, and open-label trial that looked at the efficacy and safety of gargling with PVP–I in asymptomatic-to-mild COVID-19 patients (aged ≥ 16 years) quarantined in three different locations. The protocol was approved by the Medical Center Clinical Research Review Board 1 Center for..