An Evaluation of a Synbiotic Formula for Patients With COVID-19 Infection

Study Overview
=================
Brief Summary
-----------------
In December 2019, a cluster of pneumonia cases of unidentified cause emerged in Wuhan,was identified as the culprit of this disease currently being identified as Coronavirus Disease 2019 (COVID-19) by World Health Organization. Coronavirus was found to not only target the patient's lungs but also multiple organs. Around 2-33% of Coronavirus Disease-19 patients developed gastrointestinal symptoms. Studies have shown that Severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2) was found in patient's feces, suggesting that the virus can spread through feces. In our previous study, stool samples from 15 patients with COVID-19 were analysed. Depleted symbionts and gut dysbiosis were noted even after patients were detected negative of SARS-CoV-2. A series of microbiota were correlated inversely with the disease severity and virus load. Gut microbiota could play a role in modulating host immune response and potentially influence disease severity and outcomes. The investigators are uncertain about the impact of synbiotic on patients with COVID-19. However, a therapeutic strategy aiming at investigating the gut Imicrobiota of patients with COVID-9 who take synbiotic or not, leading to lesser progression to severe disease, less hospital stay and improved quality of life.

Detailed Description
-----------------
In December 2019, a cluster of pneumonia cases of unidentified cause emerged in Wuhan, Hubei province, China. In early January, a novel betacoronavirus forming another clade within the subgenus sarbecovirus, now named SARS-CoV-2, was identified as the culprit of this disease currently being identified as Coronavirus Disease 2019 (COVID-19) by WHO. Coronavirus was found to not only target the patient's lungs, but also multiple organs. Around 2-33% of COVID-19 patients developed gastrointestinal symptoms. Studies have shown that SAR-CoV-2 was found in patient's feces, suggesting that the virus can spread through feces. In our previous study, stool samples from 15 patients with COVID-19 were analysed. Depleted symbionts and gut dysbiosis were noted even after patients were detected negative of SARS-CoV-2. A series of microbiota were correlated inversely with the disease severity and virus load. Gut microbiota could play a role in modulating host immune response and potentially influence disease severity and outcomes. In July 2020, there are more than 15 million confirmed cases globally with 620 thousand deaths. Currently, there are more than 2000 confirmed cases of COVID-19 in Hong Kong. The investigators are uncertain about the impact of synbiotic on patients with COVID-19. However, a therapeutic strategy aiming at investigating the gut Imicrobiota of patients with COVID-9 who take synbiotic or not, leading to lesser progression to severe disease, less hospital stay and improved quality of life.

Official Title
-----------------
An Evaluation of a Synbiotic Formula for Symptom Improvement in Hospitalised Patients With COVID-19 Infection

Conditions
-----------------
Covid19, Microbiota

Intervention / Treatment
-----------------
* Other: Health supplements


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Aged 18 or above; and A confirmed diagnosis of SARS-CoV-2 infection using the PCR according to the standard of according to Centre for Health Protection, Department of Health, HK at recruitment and that require admission to the hospitalization area; and Written informed consent is obtained Exclusion Criteria: Subjects admitted to Intensive Care Unit or on ventilator Known allergy or intolerance to the intervention product or its components Any known medical condition that would prevent taking oral probiotics or increase risks associated with probiotics including but not limited to inability to swallow/aspiration risk and no other methods of delivery (e.g no G/J tube) Known increased infection risk due to immunosuppression such as: Prior organ or hematopoietic stem cell transplant Neutropenia (ANC <500 cells/ul) HIV and CD4 <200 cells/ul Known history or active endocarditis Recent on CAPD or hemodialysis- Documented pregnancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Health supplements + standard care<br>28 days of health supplements (Synbiotic) daily plus standard care | Other: Health supplements<br>* 28 days of health supplements (synbiotic), 4g daily<br>|
| No Intervention: Standard care<br>No intervention | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined symptom score | Combined symptom score improvement of the first 4 weeks. Symptoms score assessment ranges from 20-80. The higher the score, the worse the symptoms. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical improvement | Compare the number and severity of symptoms existing by checking the list in symptoms assessment such as cough, shortness of breath, fever and gastrointestinal symptoms like anorexia, nausea, vomiting, abdominal pain, bloating before and during the study | 4 weeks | 
| Time to develop antibody against SARS-CoV-2 | Compare the time to develop antibody against SARS-CoV-2 in both group | 16 days | 
| Quality of life measured by EQ-5D-5L | Improvement of quality of life measured by EQ-5D-5L. EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.The index can be calculated by deducting the appropriate weights from 1, the value for full health (i.e. state 11111). Each category ranges from 1 to 5. The small the number, the better the health. The EQ-VAS is a vertical visual analogue scale that ranges 0-100 (higher score indicates better imaginable health). | 4 weeks | 
| Quality of life measured by SF-12 | Improvement of quality of life measured by SF-12. SF-12 is a self-reported outcome measure assessing the impact of health on an individual's everyday life. There are formulas for transformation of scale scores so that they will range from 0-100. High score in functioning items indicates better functioning while high score in pain items indicates freedom from pain. | 4 weeks | 
| Duration of hospital stay | Measure the duration of hospital stay in both group | up to 3 months | 
| Time to negative PCR | Compare the time to negative PCR in both group | through study completion, an average of 1 year | 
| Trend of symptom score | Trend of symptom score, ranges from 26-104. The higher the score, the worse the symptoms. | 4 weeks | 
| Gastrointestinal symptoms | Duration of gastrointestinal symptoms such as anorexia, nausea, vomiting, abdominal pain, bloating within 4 week. | 4 weeks | 
| Changes in fecal bacteria metabolites | Changes in fecal bacteria metabolites measured by PCR at different time points | weeks 2, 4, 5 and 8 months 3, 6, 9 and 12 | 
| Change in plasma cytokines level | Change in plasma cytokines level at week 2 and week 5 compared with baseline | week 2 and week 5 | 
| Changes in the gut microbiome | Changes in the gut microbiome (bacteria, virome and fungome) measured by metagenomics at different time points (weeks 1, 2, 3, 4, 5 and months 3, 6, 9 and 12) compared to baseline | weeks 1, 2, 3, 4, 5, 8 and months 3, 6, 9 and 12 | 
| Number of admission to Intensive Care Unit | Number of admission to Intensive Care Unit | 4 weeks | 
| Number of subjects with home discharge | Number of subjects with home discharge | 4 weeks | 
| Number of mortality | Number of mortality | 4 weeks | 
| Number of days absent from work | Number of days absent from work since admission | 3 months | 
| Change of quality of life questionnaire | Change in score on Quality of life using EQ-5D-5L and SF-12. EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.The index can be calculated by deducting the appropriate weights from 1, the value for full health (i.e. state 11111). Each category ranges from 1 to 5. The small the number, the better the health. The EQ-VAS is a vertical visual analogue scale that ranges 0-100 (higher score indicates better imaginable health). While the SF-12 is a self-reported outcome measure assessing the impact of health on an individual's everyday life. There are formulas for transformation of scale scores so that they will range from 0-100. High score in functioning items indicates better functioning while high score in pain items indicates freedom from pain. | week 8, months 3, 6, 9 and 12 | 
| Number of adverse event | Number of adverse event | 3 months |