Daily Lactobacillus Probiotic versus Placebo in COVID-19-Exposed Household Contacts (PROTECT-EHC): A Randomized Clinical Trial
MD Paul E Wischmeyer, Helen Tang, MS Yi Ren, BS Lauren Bohannon, BS Zeni E Ramirez, MD Tessa M Andermann, MD Julia A Messina, MD Julia A Sung, PhD David Jensen, PhD Sin-Ho Jung, Alexandra Artica, MHA Anne Britt, Amy Bush, MS Ernaya Johnson, BS Meagan V Lew, MS Hilary M Miller, MPH Claudia E Pamanes, MS Alessandro Racioppi, Aaron T Zhao, MD Neeraj K Surana, MD Anthony D Sung
doi:10.1101/2022.01.04.21268275
Importance: 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. Objective: To determine whether daily probiotic Lactobacillus rhamnosus GG (LGG) is effective in preventing development of symptoms of illness within 28 days of COVID-19 exposure. Design: This randomized, double-blind, placebo-controlled trial across the United States (PROTECT-EHC) enrolled in 2020-2021. Participants were followed for 60 days. Setting: 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. Participants: 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. Intervention: Participants were randomized to receive daily oral LGG or microcrystalline cellulose placebo for 28 days.
Main Outcomes and Measures: 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. Results: 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).
Conclusions and Relevance: 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 Lactobacillus probiotics have already been
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'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>',
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