UMIN-CTR Clinical Trial

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

COVID-19

Classification by specialty

Pneumology	Infectious disease	Adult

Classification by malignancy

Others

Genomic information

NO

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

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 .

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

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

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

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

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

Institute

Administration Department, Takanawa Clinic

Institute

Department

Personal name

Organization

Administration Department, Takanawa Clinic

Organization

Division

Category of Funding Organization

Self funding

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

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

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

高輪クリニック（東京都）

Date of disclosure of the study information

2020

Year

05

Month

22

Day

URL releasing protocol

Our protocol will be opened to the public in a scientific paper.

Publication of results

Unpublished

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

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 related information

Registered date

2020

Year

05

Month

21

Day

Last modified on

2021

Year

09

Month

11

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046202