Modulation of Gut Microbiota to Enhance Health and Immunity

Study Overview
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Brief Summary
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The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus is now a pandemic and has culminated major morbidity and mortality globally. Studies have shown that patients with underlying type 2 diabetes mellitus (DM), obesity, old age and hypertension had a higher risk of developing severe COVID-19 infection and mortality related to COVID-19.Emerging evidence has shown that gut microbiota plays an important role in the pathogenesis of COVID-19.

Detailed Description
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HYPOTHESIS We hypothesize that modulating the gut microbiota with a microbiome immunity formula can rebalance the gut microbiota in populations at risk of infection, like, patients with type 2 DM and elderlies and can lower the number of hospitalisation and reduce side effects associated with COVID-19 vaccination. AIM We aim to evaluate the efficacy of modulating gut microbiota with a microbiome immunity formula in vulnerable subjects (patients with underlying type 2 DM and elderlies) in improving immune functions, reducing adverse events associated with COVID-19 vaccinations and reducing hospitalisation in susceptible individuals during the COVID-19 pandemic. STUDY DESIGN This is a double-blinded, randomized, active-placebo controlled study comparing a microbiome immunity formula and placebo in enhancing immunity and reducing hospitalisation within one year. Except two kinds of subjects (Substudy 1: Patients with Type 2 DM and Substudy 2: Elderly individual) will be included in respective substudy, all other methodologies are the same. In each substudy, at least half of the recruited subjects will plan to receive COVID-19 vaccination and start to take the study products after vaccination. Recruited subjects will be randomised to receive a microbiome immunity formula or active placebo for 3 months, with another 9 months follow-up after completion of study products.

Official Title
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Modulation of Gut Microbiota to Enhance Health and Immunity of Vulnerable Individuals During COVID-19 Pandemic

Conditions
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Gut Microbiota, COVID-19 Vaccine

Intervention / Treatment
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* Dietary Supplement: Microbiome immunity formula
* Dietary Supplement: Active placebo


Participation Criteria
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Eligibility Criteria
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Substudy 1 Inclusion Criteria: Age 18 years - below 65 years A confirmed diagnosis of type 2 DM for ≥ 3 months with stable control (i.e. no change in DM medications in recent 2 months) Written informed consents obtained Exclusion Criteria: Known history of confirmed COVID-19 infection Known active sepsis or active malignancy Known increased infection risk due to underlying immunosuppressed state which includes: Prior organ or hematopoietic stem cell transplant Neutropenia with absolute neutrophil count (ANC) <500 cells/ul at the time of study inclusion Known HIV infection with CD4 <200 cells/ul at the time of study inclusion On concomitant immunosuppressants or corticosteroid at a dose of prednisolone equivalent dose 10mg or more for more than 3 months Known history or active infective endocarditis On peritoneal dialysis or haemodialysis Documented pregnancy Substudy 2 Inclusion Criteria: Age 65 years and above Written informed consents obtained Exclusion Criteria: Known history of confirmed COVID-19 infection Known active sepsis or active malignancy Known increased infection risk due to underlying immunosuppressed state which includes: Prior organ or hematopoietic stem cell transplant Neutropenia with absolute neutrophil count (ANC) <500 cells/ul at the time of study inclusion Known HIV infection with CD4 <200 cells/ul at the time of study inclusion On concomitant immunosuppressants, chemotherapies or corticosteroid at a dose of prednisolone equivalent dose 10mg or more for more than 3 months Known history or active infective endocarditis On peritoneal dialysis or haemodialysis Known active malignancy Known terminal illness with life expectancy less than 3 months

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active arm<br>Subject will be instructed to take microbiome immunity formula 2 sachets daily for a total of 12 weeks. | Dietary Supplement: Microbiome immunity formula<br>* Microbiome immunity formula contains probiotics blend (3 Bifidobacteria, 10 billion CFU per sachet)<br>|
| Placebo Comparator: Placebo arm<br>Subject will be instructed to take active placebo daily for a total of 12 weeks. | Dietary Supplement: Active placebo<br>* Active placebo contains active vitamin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events/Serious adverse events | Proportion of patients who presented with new symptoms/diseases which exerted unfavourable impacts on subjects. Serious adverse events are those adverse clinical events that resulted in hospital admission and/or death | within 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of the COVID-19 vaccine | Measured by serum neutralization assay against pseudo virus and live virus, and IgM and IgG against receptor-binding domain [RBD] and S1 | 3 months and 6 months | 
| Change in gut microbiome | Measured the gut microbiome changes by metagenomic sequencing and metabolite profiling by targeted and/or untargeted metabolites profiling | 1, 3, 6, and 12 months | 
| Changes in plasma inflammatory cytokines | Measured the inflammatory cytokines (CRP or ESR) in blood result | 3 months and 6 months | 
| Restoration of gut dysbiosis | It is defined as improvement in (i) gut microbiome composition and diversity; (ii) functional potential (i.e., MetaCyc pathway abundances); and (iii) proliferation of beneficial bacteria genus (i.e., bifidobacteria, eubacterium, roseburia and other short-chain fatty acids producers | 1, 3, 6 and 12 months | 
| Number of unscheduled hospitalisation and clinic visits | Number of unscheduled hospitalisation and clinic visits | 1, 3, 6, and 12 months | 
| Changes of quality of life | Measured the score of EQ-5D-5L which measure the health-related quality of life | 1, 3, 6, and 12 months | 
| Changes in glycaemic control | Measured by HbA1c | 1, 6 and 12 months |