Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial

DOI record: { "DOI": "10.1101/2022.01.04.21268275", "URL": "http://dx.doi.org/10.1101/2022.01.04.21268275", "abstract": "<jats:title>STRUCTURED ABSTRACT</jats:title><jats:sec><jats:title>Importance</jats:title><jats:p>The COVID-19 pandemic continues to pose unprecedented challenges to worldwide health. While vaccines are effective, supplemental strategies to mitigate the spread and severity of COVID-19 are urgently needed. Emerging evidence suggests susceptibility to infections, including respiratory tract infections, may be reduced by probiotic interventions; therefore, probiotics may be a low-risk, widely implementable modality to mitigate risk of COVID-19 disease, particularly in areas with low vaccine availability and/or uptake.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To determine whether daily probiotic<jats:italic>Lactobacillus rhamnosus</jats:italic>GG (LGG) is effective in preventing development of symptoms of illness within 28 days of COVID-19 exposure.</jats:p></jats:sec><jats:sec><jats:title>Design</jats:title><jats:p>This randomized, double-blind, placebo-controlled trial across the United States (PROTECT-EHC) enrolled in 2020-2021. Participants were followed for 60 days.</jats:p></jats:sec><jats:sec><jats:title>Setting</jats:title><jats:p>Describe the study setting to assist readers to determine the applicability of the report to other circumstances, for example, multicenter, population-based, primary care or referral center(s), etc.</jats:p></jats:sec><jats:sec><jats:title>Participants</jats:title><jats:p>Participants included individuals ≥ 1 year of age with a household contact with a recent (≤ 7 days) diagnosis of COVID-19. 182 participants were enrolled and randomized during the study period.</jats:p></jats:sec><jats:sec><jats:title>Intervention</jats:title><jats:p>Participants were randomized to receive daily oral LGG or microcrystalline cellulose placebo for 28 days.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>The primary outcome was development of symptoms within 28 days of exposure to a COVID-19-infected household contact. Stool was collected to evaluate for changes in microbiome structure.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>182 participants were enrolled and randomized during the study period. Intention-to-treat analysis showed that participants randomized to LGG were less likely to develop symptoms versus those randomized to placebo (26.4% vs. 42.9%, p=0.02). Further, LGG was associated with a statistically significant reduction in COVID-19 diagnosis (log rank p=0.049) via time-to-event analysis. Overall incidence of COVID-19 diagnosis did not significantly differ between LGG and placebo groups (8.8% vs. 15.4%, p=0.17). LGG was well-tolerated with no increased side effects versus placebo. Placebo recipients were more likely to stop the study product, temporarily or permanently, due to symptoms attributed to the study product (5.5% vs. 0%, p = 0.02).</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>Our study suggests that LGG is well-tolerated and is associated with prolonged time to development of COVID-19 infection, reduced incidence of symptoms, and changes to gut microbiome structure when used as post-exposure prophylaxis within 7 days after exposure. This preliminary work may inform the approach to prevention of COVID-19, particularly in underdeveloped nations where<jats:italic>Lactobacillus</jats:italic>probiotics have already been utilized to reduce non-COVID sepsis and infectious-morbidity. This study was limited by its remote format, which necessitated a primary endpoint of self-reported symptoms rather than laboratory-confirmed infection; further laboratory-based studies are needed to further define the efficacy of LGG in preventing COVID-19 infection, especially in larger populations and including comparison of pre-exposure vs. post-exposure prophylaxis.</jats:p></jats:sec><jats:sec><jats:title>Trial registration</jats:title><jats:p><jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/\">ClinicalTrials.gov</jats:ext-link>,<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04399252\">NCT04399252</jats:ext-link>,<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"uri\" xlink:href=\"https://clinicaltrials.gov/ct2/show/NCT04399252\">https://clinicaltrials.gov/ct2/show/NCT04399252</jats:ext-link></jats:p></jats:sec><jats:sec><jats:title>KEY POINTS</jats:title><jats:sec><jats:title>Question</jats:title><jats:p>Is daily probiotic<jats:italic>Lactobacillus rhamnosus</jats:italic>GG (LGG) effective in preventing development of symptoms of illness compatible with COVID-19 within 28 days of COVID-19 exposure compared to placebo?</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>In this randomized clinical trial that included 182 participants, the proportion who developed symptoms was 26.4% with LGG versus 42.9% with placebo, a significant difference.</jats:p></jats:sec><jats:sec><jats:title>Meaning</jats:title><jats:p>LGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure.</jats:p></jats:sec></jats:sec>", "accepted": { "date-parts": [ [ 2022, 1, 5 ] ] }, "author": [ { "affiliation": [], "family": "Wischmeyer", "given": "Paul E.", "sequence": "first" }, { "affiliation": [], "family": "Tang", "given": "Helen", "sequence": "additional" }, { "affiliation": [], "family": "Ren", "given": "Yi", "sequence": "additional" }, { "affiliation": [], "family": "Bohannon", "given": "Lauren", "sequence": "additional" }, { "affiliation": [], "family": "Ramirez", "given": "Zeni E.", "sequence": "additional" }, { "affiliation": [], "family": "Andermann", "given": "Tessa M.", "sequence": "additional" }, { "affiliation": [], "family": "Messina", "given": "Julia A.", "sequence": "additional" }, { "affiliation": [], "family": "Sung", "given": "Julia A.", "sequence": "additional" }, { "affiliation": [], "family": "Jensen", "given": "David", "sequence": "additional" }, { "affiliation": [], "family": "Jung", "given": "Sin-Ho", "sequence": "additional" }, { "affiliation": [], "family": "Artica", "given": "Alexandra", "sequence": "additional" }, { "affiliation": [], "family": "Britt", "given": "Anne", "sequence": "additional" }, { "affiliation": [], "family": "Bush", "given": "Amy", "sequence": "additional" }, { "affiliation": [], "family": "Johnson", "given": "Ernaya", "sequence": "additional" }, { "affiliation": [], "family": "Lew", "given": "Meagan V.", "sequence": "additional" }, { "affiliation": [], "family": "Miller", "given": "Hilary M.", "sequence": "additional" }, { "affiliation": [], "family": "Pamanes", "given": "Claudia E.", "sequence": "additional" }, { "affiliation": [], "family": "Racioppi", "given": "Alessandro", "sequence": "additional" }, { "affiliation": [], "family": "Zhao", "given": "Aaron T.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-9544-2551", "affiliation": [], "authenticated-orcid": false, "family": "Surana", "given": "Neeraj K.", "sequence": "additional" }, { "affiliation": [], "family": "Sung", "given": "Anthony D.", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2022, 1, 5 ] ], "date-time": "2022-01-05T19:30:14Z", "timestamp": 1641411014000 }, "deposited": { "date-parts": [ [ 2023, 11, 15 ] ], "date-time": "2023-11-15T11:03:44Z", "timestamp": 1700046224000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2024, 1, 5 ] ], "date-time": "2024-01-05T06:04:41Z", "timestamp": 1704434681482 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 17, "issued": { "date-parts": [ [ 2022, 1, 5 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2022.01.04.21268275", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2022, 1, 5 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2022, 1, 5 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2022010703551062000_2022.01.04.21268275v1.1", "unstructured": "WHO COVID-19 Dashboard. 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