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

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Covid19; Microbiota
• Intervention / Treatment: Other: Health supplements

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Hong Kong
  • Sha Tin, Hong Kong, 000000
    • The Chinese University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Aged 18 or above; and
2. 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
3. Written informed consent is obtained

Exclusion Criteria:

1. Subjects admitted to Intensive Care Unit or on ventilator
2. Known allergy or intolerance to the intervention product or its components
3. 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)

4. 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
5. Known history or active endocarditis
6. Recent on CAPD or hemodialysis-
7. Documented pregnancy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Health supplements + standard care; 28 days of health supplements (Synbiotic) daily plus standard care	Other: Health supplements; 28 days of health supplements (synbiotic), 4g daily
No Intervention: Standard care; 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

Collaborators and Investigators

• Sponsor: Siew Chien NG

Publications and helpful links

General Publications

• Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24. Erratum In: Lancet. 2020 Jan 30;:
• Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W; China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-733. doi: 10.1056/NEJMoa2001017. Epub 2020 Jan 24.
• Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
• Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, Ericson K, Wilkerson S, Tural A, Diaz G, Cohn A, Fox L, Patel A, Gerber SI, Kim L, Tong S, Lu X, Lindstrom S, Pallansch MA, Weldon WC, Biggs HM, Uyeki TM, Pillai SK; Washington State 2019-nCoV Case Investigation Team. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020 Mar 5;382(10):929-936. doi: 10.1056/NEJMoa2001191. Epub 2020 Jan 31.
• Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol. 2004 Apr;136(1):95-103. doi: 10.1111/j.1365-2249.2004.02415.x.
• Janowitz T, Gablenz E, Pattinson D, Wang TC, Conigliaro J, Tracey K, Tuveson D. Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalised patients: a case series. Gut. 2020 Sep;69(9):1592-1597. doi: 10.1136/gutjnl-2020-321852. Epub 2020 Jun 4.
• Docherty AB, Harrison EM, Green CA, Hardwick HE, Pius R, Norman L, Holden KA, Read JM, Dondelinger F, Carson G, Merson L, Lee J, Plotkin D, Sigfrid L, Halpin S, Jackson C, Gamble C, Horby PW, Nguyen-Van-Tam JS, Ho A, Russell CD, Dunning J, Openshaw PJ, Baillie JK, Semple MG; ISARIC4C investigators. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020 May 22;369:m1985. doi: 10.1136/bmj.m1985.
• Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020 Apr;5(4):335-337. doi: 10.1016/S2468-1253(20)30048-0. Epub 2020 Feb 20. No abstract available.
• Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, Zhang Q, Qi W. Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus. Gut. 2020 Jun;69(6):1141-1143. doi: 10.1136/gutjnl-2020-320832. Epub 2020 Feb 26. No abstract available.
• Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, Sigl V, Hanada T, Hanada R, Lipinski S, Wild B, Camargo SM, Singer D, Richter A, Kuba K, Fukamizu A, Schreiber S, Clevers H, Verrey F, Rosenstiel P, Penninger JM. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012 Jul 25;487(7408):477-81. doi: 10.1038/nature11228.
• Zuo T, Zhan H, Zhang F, Liu Q, Tso EYK, Lui GCY, Chen N, Li A, Lu W, Chan FKL, Chan PKS, Ng SC. Alterations in Fecal Fungal Microbiome of Patients With COVID-19 During Time of Hospitalization until Discharge. Gastroenterology. 2020 Oct;159(4):1302-1310.e5. doi: 10.1053/j.gastro.2020.06.048. Epub 2020 Jun 26.
• WHO Coronavirus Disease (COVID-19) Dashboard. [Assessed on 24 Jul 2020]. https://covid19.who.int/
• Latest situation of cases of COVID-19. [Assessed on 24 Jul 2020]. https://www.chp.gov.hk/files/pdf/local_situation_covid19_en.pdf

Study record dates

Study Major Dates

• Study Start (Actual): August 13, 2020
• Primary Completion (Actual): December 31, 2021
• Study Completion (Anticipated): July 31, 2023

Study Registration Dates

• First Submitted: August 11, 2020
• First Submitted That Met QC Criteria: October 6, 2020
• First Posted (Actual): October 9, 2020

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: Synbiotic COV study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No