Antiseptic Mouthwash / Pre-Procedural Rinse on SARS-CoV-2 Load (COVID-19)

Study Overview
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Brief Summary
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In this pilot trial, 150 confirmed COVID-19 individuals will be randomly assigned to 1 of 5 groups: distilled water, CloSYS Ultra Sensitive Rinse (Rowpar Pharmaceutical Inc., USA), Oral-B Mouth Sore (Oral-B, USA), Crest Pro-Health Multi-Protection (Crest, USA), or Listerine Zero (Johnson and Johnson, USA). Study participants will be asked to rinse/gargle with 10-20ml (according to the rinse instructions) of the assigned solutions 4 times per day, for 30-60 seconds, for 4 weeks.

Detailed Description
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SARS-CoV-2, the virus causing COVID-19, has affected vulnerable individuals, especially those with comorbidities, and high exposure health care workers (HCWs). Typically, the virus first colonizes in the upper respiratory tract (URT) causing clinical symptoms such as coughing, sore throat, and then is transferred to the lower respiratory tract (LRT) which can lead to severe pneumonia, acute respiratory distress syndrome (ARDS), sepsis, and death, if it is not managed. The World Health Organization (WHO) has presented comprehensive guidelines underscoring personal hygiene measures including respiratory hygiene against SARS, MERS, influenza, and now SARS-CoV-2 / COVID-19. While personal protection equipment (PPE), personal hygiene measures, environmental infection control, and physical distancing are crucial in mitigating disease transmission, respiratory hygiene measures do not prevent SARS-CoV-2 colonization in URTs and LRTs of infected individuals (symptomatic and asymptomatic). Experimental and clinical research studies on infections similar to COVID-19 such as SARS, MERS, and H5N1 have shown that using antiseptic mouthwash/gargling solutions, such as products containing chlorhexidine gluconate (CHG), polyvinylpyrrolidone iodine (PVP-I), chlorine dioxide (ClO2), cetylpyridinium chloride (CPC), and hydrogen peroxide (H2O2) can reduce viral load. A randomized controlled trial (N=387) showed efficacy and cost-effectiveness of gargling with water or a product containing PVP-I (3X/day, 20 seconds) on URTIs in healthy volunteers (18-65 years) over 60 days from a societal perspective; in vitro studies have shown that CloSYS, an over the counter mouthwash containing ClO2, was effective on inactivating SARS-CoV as well as disinfecting dental unit waterlines, and biofilm control in ultrasonic dental scaling units. A recent study has shown that CloSYS Ultra Sensitive Oral Rinse reduced the viral load of SARS CoV 2, SARS CoV, and Influenza A H3N2 to a varying extent. The data show that the viral load reduction of SARS CoV 2 by Ultra Sensitive rinse was 10 fold more than the reduction of SARS CoV in 30s. Recently, the US Centers for Disease Control (CDC) and the American Dental Association (ADA) have recommended using a mouthwash containing 1.0-1.5% H2O2 as a pre-procedural rinse before dental treatment to potentially reduce SARS-CoV-2 load; however, no in vivo clinical studies have been conducted to support this claim. The aim of this pilot trial is to evaluate the effect of four over-the-counter antiseptic mouthwash/gargling solutions compared to a control (distilled water) to reduce SARS-CoV-2 load. In addition, study participants will be assessed for the severity of their clinical symptoms during the study period. The 4-week protocol was selected as studies have shown that patients can continue to shed the virus and potentially transmit it to the others for a 2 to 4 week period. An interim analysis is planned when 10 participants per arm (50 total) complete the study using the alpha-spending function with O'Brien-Fleming boundary rule.

Official Title
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Effect of Antiseptic Mouthwash/Gargling Solutions and Pre-procedural Rinse on SARS-CoV-2 Load (COVID-19)

Conditions
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COVID-19, SARS-CoV 2, Severe Acute Respiratory Syndrome Coronavirus 2, Virus Disease, Coronavirus Infections, Pharyngeal Diseases

Intervention / Treatment
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* Drug: Oral-B Mouth Sore mouthwash
* Drug: Crest Pro-Health Multi-Protection mouthwash
* Drug: CloSYS Ultra Sensitive Rinse mouthwash
* Drug: Distilled water
* Drug: Listerine Zero Mouthwash Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Tested positive for COVID-19 with a sample collected in the prior 7 days Ability to read and speak English or Spanish Ability to participate in the study for 4 weeks Being asymptomatic or having mild or moderate symptoms (for example, sore throat, coughing, fever, fatigue) Ability to rinse/gargle Not having any condition that might worsen with gargling solutions Not having a history of mouthwash sensitivity Not having an allergy to any mouthwash that has been used before Not using another mouthwash/gargling solution since the most recent positive test Not taking antimicrobial medications (antibacterial, antiviral, antibiotics including off-label FDA-approved medications such as hydroxychloroquine) Anticipated ability to participate in the study for 4 weeks Have a cellphone and agree to receive text messages for reminders to use mouthwash during the day and for follow-up visits, and can videoconference (like zoom) on a cellphone, tablet, or computer for sample collection instructions Exclusion Criteria: People who because of their symptoms intend to receive antiviral medications that could potentially affect viral load in their saliva samples Pregnant or lactating women due to potential aversions to mouthwash solution taste/smell.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A blinded randomized controlled parallel group design trial
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control (Distilled Water)<br>Over the counter: Distilled water | Drug: Distilled water<br>* Rinse and gargle 4 times daily, for 60 seconds, for 4 weeks.<br>* Other names: H2O;|
| Experimental: Oral-B Mouth Sore (H2O2) mouthwash<br>Over the counter: Oral-B Mouth Sore (Oral-B, USA) contains hydrogen peroxide (H2O2) | Drug: Oral-B Mouth Sore mouthwash<br>* Rinse and gargle 4 times daily, for 60 seconds, for 4 weeks.<br>* Other names: H2O2;|
| Experimental: Crest Pro-Health Multi-Protection (C21H38ClN) mouthwash<br>Over the counter: Crest Pro-Health Multi-Protection (Crest, USA) contains cetylpyridinium chloride (C21H38ClN) | Drug: Crest Pro-Health Multi-Protection mouthwash<br>* Rinse and gargle 4 times daily, for 60 seconds, for 4 weeks.<br>* Other names: C21H38ClN;|
| Experimental: CloSYS (ClO2) mouthwash<br>Over the counter: CloSYS Ultra Sensitive Rinse (Rowpar Pharmaceutical Inc., USA) contains stabilized chlorine dioxide (ClO2) | Drug: CloSYS Ultra Sensitive Rinse mouthwash<br>* Rinse and gargle 4 times daily, for 45 seconds, for 4 weeks.<br>* Other names: ClO2;|
| Experimental: Listerine Mouthwash<br>Over the counter: Listerine Zero (Alcohol-Free)(Johnson and Johnson, USA) (C30H52O3) | Drug: Listerine Zero Mouthwash Product<br>* Rinse and gargle 4 times daily, for 30 seconds, for 4 weeks.<br>* Other names: alcohol-free;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in SARS-CoV-2 Viral Load | The change in the outcome measure, SARS-CoV-2 viral load, in saliva wash RT-PCR was measured by Cycle Threshold (Ct) value. Ct value refers to the number of cycles it takes for the fluorescent signal generated during the PCR reaction to cross a certain threshold, indicating the presence of the target nucleic acid sequence, here, SARS-CoV-2. The lower the Ct value, the faster the threshold is crossed and the higher the viral load in a biological sample, suggesting a higher concentration of the SARS-CoV-2 virus in that sample. | Baseline to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Self-reported Clinical Symptom(s) | Any self-reported (questionnaire) clinical symptom(s). A symptom checklist included cough, runny nose, scratchy/sore throat, fever, chills, fatigue, muscle ache, shortness of breath, diarrhea/nausea/vomiting, loss of taste/smell, and red /painful eye. (Clinical symptoms were collected at baseline and at 3 months; only problems with the study mouth rinse were collected daily through 4 weeks.) | Baseline to 3 months | 
| Any Hospitalization(s) | Any hospitalization(s) from baseline to 4 weeks. Hospitalization(s) were collected on adverse event, unanticipated problem, and final disposition forms. | Baseline to 4 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anti-Infective Agents, Local, Mouthwashes, Gargle, Saliva