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

  1. Paul E. Wischmeyer
  2. Helen Tang
  3. Yi Ren
  4. Lauren Bohannon
  5. Zeni E. Ramirez
  6. Tessa M. Andermann
  7. Julia A. Messina
  8. Julia A. Sung
  9. David Jensen
  10. Sin-Ho Jung
  11. Alexandra Artica
  12. Anne Britt
  13. Amy Bush
  14. Ernaya Johnson
  15. Meagan V. Lew
  16. Hilary M. Miller
  17. Claudia E. Pamanes
  18. Alessandro Racioppi
  19. Aaron T. Zhao
  20. Neeraj K. Surana
  21. Anthony D. Sung

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Abstract

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 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 registration

ClinicalTrials.gov , NCT04399252 , https://clinicaltrials.gov/ct2/show/NCT04399252

KEY POINTS

Question

Is 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?

Findings

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.

Meaning

LGG probiotic may protect against the development of symptoms when used as post-exposure prophylaxis within 7 days after COVID-19 exposure.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2022.01.04.21268275: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsField Sample Permit: This research was conducted under Food and Drug Administration Investigational New Drug Application 24777; the research protocol was approved by the Duke University Institutional Review Board, registered on ClinicalTrials.gov (NCT04399252), and was previously published.
    IRB: This research was conducted under Food and Drug Administration Investigational New Drug Application 24777; the research protocol was approved by the Duke University Institutional Review Board, registered on ClinicalTrials.gov (NCT04399252), and was previously published.
    Consent: 18 All participants provided documented informed consent.
    Sex as a biological variablenot detected.
    RandomizationTrial design: Participants were randomized using a permuted block randomization technique to receive LGG or placebo in a 1:1 ratio.
    BlindingBoth subjects and study coordinators are blinded to the intervention; the randomization key was generated by the study statistician and only the pharmacist dispensing the study product had access to the key.
    Power AnalysisPre-study sample size was calculated assuming an attack rate of 10.5% in household contacts based on CDC reports.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Data Collection: Data on demographics, medical history, household risks, and infection details of index patient were collected remotely upon enrollment via REDCap, an electronic platform that supports secure data capture for research.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    23 After demultiplexing, DADA2 was used for quality control and to generate a count table,24 and taxonomy was assigned using the Silva v138.1 database.
    Silva
    suggested: (SILVA, RRID:SCR_006423)
    Data analysis was performed using the R programming suite packages phyloseq and ggplot2.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    All analyses were performed in SAS 9.4 (SAS Institute, Cary, NC).
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study has several limitations. First, we were limited by a smaller-than-expected sample size due to difficulty with recruitment during concurrent vaccine rollout, which increasingly limited the eligible population and our statistical power. Given the high transmissibility of newer viral strains and potential for waning vaccine efficacy, future studies may consider including vaccinated individuals, especially as data suggest that probiotic administration improves vaccination efficacy against other viral pathogens, such as influenza.30 Further, while allocation was blinded and randomized in a 1:1 fashion, participants in the placebo group had a small increased incidence of current smoking and hypertension at baseline, which are potential risk factors for development of COVID-19 disease; however, smoking was not associated with development of symptoms in our study. Additionally, LGG and other probiotics may be associated with gastrointestinal side effects, potentially confounding our measurement of symptoms, although fewer GI side effects were noted in the probiotic group. Another limitation was the remote format, wherein the primary endpoint was self-reported symptoms rather than laboratory-confirmed infection; participants had inconsistent access to laboratory testing, with only 61% of symptomatic participants ultimately undergoing testing. In conclusion, COVID-19 continues to pose a unique and novel challenge to global health.5 We conducted the first double-blinded, rando...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04399252CompletedEffect of Lactobacillus on the Microbiome of Household Conta…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2022.01.04.21268275v1 on medRxiv