Clinical trial NCT05083572: Effect of Probiotic on Gut Microbiome and Bacterial Translocation in Healthy Asian Volunteers
Official title: Effect of Probiotic (Vivomixx/ DeSimone Formulation) on Gut Microbiome and Bacterial Translocation in Healthy Asian Volunteers - An Exploratory Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Dysbiosis
Keywords: Gut microbiome
Probiotic
Bacterial translocation
Lead sponsor: Changi General Hospital
Sponsor class: OTHER
First posted: 2021-10-19
Enrollment: 32
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Dysbiosis of the gut microbiome has been recognized to underlie the pathogenesis of various gastrointestinal conditions. Probiotics are known to exert beneficial effects on gut health and have great potential for use as microbiome interventions for gastrointestinal and metabolic diseases. While it is widely known that probiotic bacteria favourably alter the intestinal microflora balance, their other mechanisms of action have not been systematically characterized. The ability of probiotics to modulate dysbiosis may lead to reduced levels of endotoxaemia and oxidative stress. In this study, the investigators propose to examine the effects of 4-week Vivomixx treatment on the gut microbiome and bacterial translocation in healthy Asian volunteers with and without colonic lavage or antibiotic treatment. The study will also examine the same outcome parameters 4 weeks upon cessation of the product. The findings derived from the study will provide valuable insights into the microbiota changes associated with colonic lavage or antibiotic treatment, and the use of probiotic (Vivomixx). This has important clinical implications in designing treatment strategies in clinical practice such as the use of Vivomixx as microbiome interventions with antibiotics which are known to induce Clostridium difficile-associated diarrhoea, as well as in the therapeutic management of various diseases associated with dysbiosis.

Detailed description: This will be a randomized controlled, partially-blinded study with four study arms to (i) examine the effect of Vivomixx on the gut microbiome with and without colonic lavage, (ii) with and without antibiotic treatment, (iii) compare the gut microbiome after natural recovery and with Vivomixx treatment following colonic lavage, and (iv) evaluate the efficacy of Vivomixx in reducing bacterial translocation and oxidative stress.

Screening Visit Procedures (within 28 days of first dosing):

* Informed consent;
* Demography, including date of birth, sex, and race/ethnicity;
* Body weight and height measurement;
* Determination of eligibility based on inclusion/exclusion criteria;
* Adverse event/concomitant medication check;
* Complete medical/drug history;
* Alcohol/Smoking history;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes;
* Complete physical examination;
* Laboratory safety tests (liver panel, renal panel and complete blood count) (10 ml blood);
* Urine dipstick pregnancy test (for female subjects only).

Day -14 Procedures (for Group D only):

On reporting to CTRU on Day -14, participants will be reminded of study restrictions and undergo the following assessments:

* Interim medical/drug history;
* Adverse event/concomitant medication check;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes;
* Complete physical examination;
* Provision of baseline stool sample \~3g (before dosing with rifaximin) (for microbiome and SCFA);
* Provision of baseline blood sample \~12ml for flow cytometry and SCFA analysis (before dosing with rifaximin);
* Rifaximin on-site dosing;
* Rifaximin dispensing for home consumption (1 tablet 200mg daily till Day -7).

Day -7 Procedures (for Group D only):

On reporting to CTRU on Day -7, participants will be reminded of study restrictions and undergo the following assessments:

* Interim medical/drug history;
* Adverse event/concomitant medication check;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes;
* Brief physical examination;
* Provision of stool sample \~3g (for microbiome and SCFA);
* Provision of blood sample \~12ml for flow cytometry and SCFA analysis;
* Rifaximin home dosing (1 tablet 200mg in morning);
* Return of rifaximin for accountability check;
* Rifaximin dispensing for home consumption (1 tablet 200mg daily till Day 1).

Day -1 Procedures (for Groups A \& B only):

On reporting to CTRU on Day -1, participants will be reminded of study restrictions and undergo the following assessments:

* Interim medical/drug history;
* Adverse event/concomitant medication check;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes;
* Complete physical examination;
* Provision of baseline stool sample \~3g (before dosing with PEG) (for microbiome and SCFA);
* Provision of baseline blood sample \~12ml for flow cytometry and SCFA analysis (before dosing with PEG);
* PEG dispensing for colonic lavage (home consumption- 2L at 6pm);
* Telephone call at night for bowel movement and AE check.

Day 1 Procedures:

• Home consumption of 2L PEG at 6am for colonic lavage.

On reporting to CTRU on Day 1, participants will be reminded of study restrictions and undergo the following assessments:

* Interim medical/drug history (for Group C only);
* Adverse event/concomitant medication check;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes (for Group C only);
* Complete physical examination;
* Verbal stool symptom assessment (for Group D only);
* Laboratory safety tests (liver panel, renal panel and complete blood count) (10 ml blood) (for Group D only);
* Biomarker test (5 ml blood before dosing) (for Group C only);
* Endotoxaemia test (5 ml blood 2hrs post-meal) (for Group C only);
* Provision of stool sample \~3g (before dosing with Vivomixx or Placebo) (for microbiome and SCFA);
* Provision of blood sample \~12ml for flow cytometry and SCFA analysis (before dosing with Vivomixx or Placebo);
* Vivomixx (Groups A, C \& D) or Placebo (Group B) on-site dosing;
* Return of PEG (Groups A \& B) or rifaximin (Group D) for accountability check;
* Vivomixx or Placebo dispensing for home consumption.

Day 2-28 Procedures:

* Self-administration of 2 capsules of Vivomixx (Groups A, C \& D) or Placebo (Group B) twice daily (morning and evening) till Day 28;
* Consumption of the study products will be monitored real-time via electronic means on mobile devices (video call). All morning dosing should be between 8-10am, and all evening dosing should happen between 6-8pm;
* Verbal stool symptom assessment on Day 14.

Day 29 Procedures (+ 2 days):

On reporting to CTRU on Day 29, participants will be reminded of study restrictions and undergo the following assessments:

* Adverse event/concomitant medication check;
* Blood pressure, heart rate and temperature, taken after resting at a sitting position for at least 5 minutes;
* Verbal stool symptom assessment;
* Complete physical examination;
* Laboratory safety tests (liver panel, renal panel and complete blood count) (10 ml blood);
* Biomarker and endotoxaemia tests (10 ml blood) (for Group C only);
* Provision of stool sample \~3g (for microbiome and SCFA);
* Provision of blood sample \~12ml for flow cytometry and SCFA analysis;
* Vivomixx (Groups A, C \& D) or Placebo (Group B) home dosing (2 capsules in morning and evening);
* Return of Vivomixx (Groups A, C \& D) or Placebo (Group B) for accountability check.

Day 56 Procedures (± 3 days) (Final Visit):

* Adverse event/concomitant medication check;
* Brief physical examination;
* Verbal stool symptom assessment;
* Provision of stool sample \~3g (for microbiome and SCFA);
* Provision of blood sample \~12ml for flow cytometry and SCFA analysis.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed written informed consent,
2. Aged between 21-65 years of age,
3. Chinese, Malay or Indian ancestry through three generations,
4. Body Weight ≥ 50kg, Body Mass Index (BMI) of 18.5 to 29.9 kg/m2, inclusive,
5. Clinical laboratory assessment results within normal limits, unless the deviation is considered not clinically significant by the investigator,
6. Regular stool every 1-2 days,
7. Satisfactory medical assessment as assessed by physical examination, medical history, and normal laboratory values or minor variations that are not clinically significant,
8. Ability to communicate with the investigator and to understand and comply with all requirements of study participation.
9. Both male and female participants (with child-bearing potential) and their partners have to practise contraception throughout the duration of the study.

Exclusion Criteria:

1. Any acute illness within 14 days of first dosing, unless otherwise approved by the PI,
2. History or evidence of clinically significant hepatic, renal, cardiovascular, respiratory, gastrointestinal, immunosuppressive or metabolic disorders, any cancer types,
3. Declare themselves positive for HIV or viral hepatitis (Hepatitis A, B, C),
4. Treatment within the previous 3 months with antibiotics (subjects are to inform study staff should they be prescribed antibiotics during the course of the study)
5. Treatment with any prescription or over-the-counter medications, complementary health products, or herbal supplements within 28 days of first dosing,
6. Consumption of probiotics or lactobacillus-containing products e.g. Yakult, Vitagen or Yogurt within 4 weeks of first dosing unless approved by the PI,
7. Abnormal biochemistry indicators, unless certified as not clinically significant,
8. Poor peripheral venous access,
9. Irregular bowel habits or complains of constipation problem,
10. Pregnancy or lactation,
11. Known allergic reactions to rifaximin, PEG or Vivomixx,
12. History of drug/alcohol abuse,
13. Involvement in the planning or conduct of this study.

Primary outcomes:
measure: Microbiome profile using 16S rRNA sequencing
timeFrame: 2 to 2.5 months
measure: Inflammatory cytokines using ELISA tests
timeFrame: 2 to 2.5 months
measure: Bacterial translocation using endotoxin assay
timeFrame: 2 to 2.5 months
Secondary outcomes:
measure: Peripheral blood lymphocyte phenotyping using flow cytometry
timeFrame: 2 to 2.5 months
measure: Short chain fatty acids using mass spectrometry
timeFrame: 2 to 2.5 months
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: Changi General Hospital
Study officials:
affiliation: Changi General Hospital
name: Tiing Leong Ang
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jalanka J, Salonen A, Salojarvi J, Ritari J, Immonen O, Marciani L, Gowland P, Hoad C, Garsed K, Lam C, Palva A, Spiller RC, de Vos WM. Effects of bowel cleansing on the intestinal microbiota. Gut. 2015 Oct;64(10):1562-8. doi: 10.1136/gutjnl-2014-307240. Epub 2014 Dec 19.
citation: Valentini L, Pinto A, Bourdel-Marchasson I, Ostan R, Brigidi P, Turroni S, Hrelia S, Hrelia P, Bereswill S, Fischer A, Leoncini E, Malaguti M, Blanc-Bisson C, Durrieu J, Spazzafumo L, Buccolini F, Pryen F, Donini LM, Franceschi C, Lochs H. Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota - The "RISTOMED project": Randomized controlled trial in healthy older people. Clin Nutr. 2015 Aug;34(4):593-602. doi: 10.1016/j.clnu.2014.09.023. Epub 2014 Oct 8.