UMIN-CTR Clinical Trial

Basic information
Public title	Immunological efficacy of lactic acid bacteria for COVID-19
Acronym	COVID-19/lactic acid bacteria
Scientific Title	Immunological efficacy of lactic acid bacteria for COVID-19: an open-label trial
Scientific Title:Acronym	COVID-19/lactic acid bacteria
Region	Japan

Condition
Condition	COVID-19
Classification by specialty	Pneumology Infectious disease Adult
Classification by malignancy	Others
Genomic information	NO

Objectives
Narrative objectives1	A rapid increase in the numbers of patients with and deaths from COVID-19 is becoming a global threat to public health. One of the reasons for the current pandemic is that effective vaccine or specific drugs against COVID-19 remain unavailable. Previous studies have shown that intake of lactic acid bacteria has a preventive effect on the infection of influenza virus. However, the feasibility of prophylactic use against COVID-19 has not been confirmed. We thus examine whether hematological and immunological measures of healthy individuals are affected by the administration of lactic acid bacteria.
Basic objectives2	Efficacy
Basic objectives -Others
Trial characteristics_1
Trial characteristics_2
Developmental phase

Assessment
Primary outcomes	Plasma cytokine levels after the administration of lactic acid bacteria for 7 days .
Key secondary outcomes	Hematology and blood biochemistry after the administration of lactic acid bacteria for 7 days .

Base
Study type	Interventional

Study design
Basic design	Single arm
Randomization	Non-randomized
Randomization unit
Blinding	Open -no one is blinded
Control	Uncontrolled
Stratification
Dynamic allocation
Institution consideration
Blocking
Concealment

Intervention
No. of arms	1
Purpose of intervention	Prevention
Type of intervention	Food
Interventions/Control_1	Using the lactic acid bacteria suitability assay, the best- and worst-matched species are selected for each subject from the following three species of lactic acid bacteria: Lactobacillus plantarum, Bifidobacterium longum, and Lactococcus lactis ssp. lactis, which have been shown to be effective for the prevention of influenza in previous studies. The subjects are instructed to take the species (granular powder) in accordance with the following protocol. Duration: 3 weeks (the best-matched species for 1 week, washout for 1 week, and the worst-matched species for 1 week) Dose: one-hundred billion (heat-killed bacteria)/day Frequency: twice daily, morning and night at 12-hour intervals Blood sampling: 3 times
Interventions/Control_2
Interventions/Control_3
Interventions/Control_4
Interventions/Control_5
Interventions/Control_6
Interventions/Control_7
Interventions/Control_8
Interventions/Control_9
Interventions/Control_10

Eligibility
Age-lower limit	20 years-old <=
Age-upper limit	70 years-old >
Gender	Male and Female
Key inclusion criteria	Healthy volunteers
Key exclusion criteria	1) Current infectious, inflammatory, or immune-related diseases 2) Pregnant female
Target sample size	30

Research contact person
Name of lead principal investigator	1st name Tsutomu Middle name Last name Nakamura
Organization	Institute for Quantitative Biosciences, The University of Tokyo
Division name	Laboratory of Molecular and Genetic Information
Zip code	113-0032
Address	1-1-1, Yayoi, Bunkyo-ku, Tokyo
TEL	03-5841-7834
Email	nakamurachibiko@gmail.com

Public contact
Name of contact person	1st name Tomoka Middle name Last name Ebisui
Organization	Takanawa Clinic
Division name	Administration Department
Zip code	140-0001
Address	1-22-17, Kitashinagawa, Shinagawa-ku, Tokyo
TEL	03-6433-3165
Homepage URL
Email	jimukyoku@takanawa-clinic.com

Sponsor
Institute	Administration Department, Takanawa Clinic
Institute
Department

Funding Source
Organization	Administration Department, Takanawa Clinic
Organization
Division
Category of Funding Organization	Self funding
Nationality of Funding Organization

Other related organizations
Co-sponsor
Name of secondary funder(s)

IRB Contact (For public release)
Organization	Research Ethics Committee of Takanawa Clinic
Address	1-22-17, Kitashinagawa, Shinagawa-ku, Tokyo
Tel	03-6712-9747
Email	support@idou-medical.jp

Secondary IDs
Secondary IDs	NO
Study ID_1
Org. issuing International ID_1
Study ID_2
Org. issuing International ID_2
IND to MHLW

Institutions
Institutions	高輪クリニック（東京都）

Other administrative information
Date of disclosure of the study information	2020 Year 05 Month 22 Day

Related information
URL releasing protocol	Our protocol will be opened to the public in a scientific paper.
Publication of results	Unpublished

Result
URL related to results and publications	Our findings will be opened to the public in a scientific paper.
Number of participants that the trial has enrolled	20
Results	L. plantarum showed the strikingly high innate cytokine index in all subjects in the in vitro cytokine response assay. In the subsequent trial, oral L. plantarum significantly increased the innate cytokine index and decreased the plasma level of IL-6. The cytokine index increased in 16 of 18 subjects with considerable individual differences in the fold change. In line with these innate cytokine changes, L. plantarum ingestion significantly enhanced the activity of natural killer cells.
Results date posted	2021 Year 09 Month 11 Day
Results Delayed
Results Delay Reason
Date of the first journal publication of results
Baseline Characteristics	18 healthy adult subjects (1 male, 17 females; ages 28-66 years; mean age [SD], 44.2 [10.1] years) completed the intervention. They had no recorded and reported comorbidities and were negative for PCR and IgM/IgG antibodies tests for SARS-CoV-2 at study entry (i.e. no previous and current SARS-CoV-2 infection).
Participant flow	A total of 20 volunteers were screened for eligibility, found to be eligible, and enrolled in this trial. LAB species were administered to all the enrolled participants, 2 of whom were excluded from the main analysis due to no visit to our clinic after the LAB prescription. Consequently, 18 subjects completed the intervention, and the data were subjected to the statistical analysis.
Adverse events	No adverse events were observed during this study period.
Outcome measures	The primary outcome measure Oral intake of L. plantarum significantly increased plasma IL-1beta (median [IQR]: 0.00 [0.00-0.00] vs 0.134 [0.0915-0.292] pg/mL; P = 0.0000310 in the Friedman test; P = 0.00284 in the post hoc Nemenyi test) and decreased plasma IL-6 (median [IQR]: 1.18 [0.812-2.13] vs 0.495 [0.425-0.775] pg/mL; P = 0.0131 in the Friedman test; P = 0.0128 in the post hoc Nemenyi test). There were no significant differences in the plasma levels of TNF-alpha, IL-18, and IL-8. Consequently, the QICI value was significantly increased (mean fold change: 16.8-fold; median [IQR]: 1760 [680-3550] vs 12300 [5440-42200]; P = 0.0173 in the Friedman test; P = 0.0138 in the post hoc Nemenyi test). The QICI values were increased in 16 of 18 subjects (88.9%) with considerable individual differences in the fold change (1.06-128-fold, mean fold change: 18.8-fold), suggesting that there are large variations in responsiveness to L. plantarum among individuals. In contrast, oral intake of B. longum induced a significant decrease in plasma IL-1beta (median [IQR]: 0.134 [0.0915-0.292] vs 0.00 [0.00-0.00] pg/mL; P = 0.0000310 in the Friedman test; P = 0.000706 in the post hoc Nemenyi test); however, the QICI value did not change significantly (mean fold change: 1.54-fold; median [IQR]: 12300 [5440-42200] vs 2780 [940-9820]; P = 0.0173 in the Friedman test; P = 0.474 in the post hoc Nemenyi test). The QICI values increased in 8 of 18 subjects (44.4%), but the fold changes were markedly lower (1.20-8.58-fold, mean fold change: 3.30-fold) than those obtained during the L. plantarum session. The secondary outcome measure We found that L. plantarum ingestion caused a minor but significant change in mean corpuscular hemoglobin concentration (median [IQR]: 33.3 [32.4-33.9] vs 32.6 [32.1-33.1] %; P = 0.00456 in the Friedman test; P = 0.00836 in the post hoc Nemenyi test). No significant changes in the hematological parameters were observed during the B. longum session.
Plan to share IPD
IPD sharing Plan description

Progress
Recruitment status	Completed
Date of protocol fixation	2020 Year 04 Month 26 Day
Date of IRB	2020 Year 05 Month 07 Day
Anticipated trial start date	2020 Year 05 Month 22 Day
Last follow-up date	2020 Year 06 Month 30 Day
Date of closure to data entry
Date trial data considered complete
Date analysis concluded

Other
Other related information

Management information
Registered date	2020 Year 05 Month 21 Day
Last modified on	2021 Year 09 Month 11 Day

Link to view the page
URL(English)	https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046202

Research Plan
Registered date	File name

Research case data specifications
Registered date	File name

Research case data
Registered date	File name

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