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

STRUCTURED ABSTRACTO_ST_ABSImportanceC_ST_ABSThe 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. ObjectiveTo determine whether daily probiotic Lactobacillus rhamnosus GG (LGG) is effective in preventing development of symptoms of illness within 28 days of COVID-19 exposure. DesignThis randomized, double-blind, placebo-controlled trial across the United States (PROTECT-EHC) enrolled in 2020-2021. Participants were followed for 60 days. SettingDescribe 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. ParticipantsParticipants 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. InterventionParticipants were randomized to receive daily oral LGG or microcrystalline cellulose placebo for 28 days. Main Outcomes and MeasuresThe 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. Results182 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 RelevanceOur 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 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. Trial registrationClinicalTrials.gov, NCT04399252, https://clinicaltrials.gov/ct2/show/NCT04399252 KEY POINTSO_ST_ABSQuestionC_ST_ABSIs daily probiotic Lactobacillus rhamnosus GG (LGG) effective in preventing development of symptoms of illness compatible with COVID-19 within 28 days of COVID-19 exposure compared to placebo? FindingsIn 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. MeaningLGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure.