The Effect of Probiotic Supplementation

End Stage Renal Disease Clinical Trial

Official title:

Daily Intake of Lactobacillus Casei Shirota (LcS) Modulates Intestinal Permeability and Decreases Circulating Levels of Endotoxin That Associate With Both Cardiovascular and All-cause Mortality in Haemodialysis Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04390347
• Other study ID #: 0760
• Status: Active, not recruiting
• Phase: N/A
• Start date: October 20, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: May 2023
• Source: University of Leicester
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a double-blind randomised controlled trial where participants will be randomised to either twice daily 65ml of Lactobacillus casei Shirota for six months or a matched placebo.

Description:

Intervention

The intervention product (Yakult) (supplied as fermented milk) and placebo will be delivered in sealed pots of 65 mL with date stamped expiry. Yakult contains Lactobacillus casei Shirota (a minimum of 6.5 × 10 9 live cells of Lactobacillus casei Shirota are contained in each pot). The pots will be stored at 4-7 °C (domestic refrigerator) on premises at University Hospital of Leicester and the University of Leicester until provided to participants. These products have a shelf life of four weeks but fresh deliveries will be sent every two weeks. They will be stored at approximately seven degrees Celsius (refrigerated at the University and subsequently, after delivery to participants, in domestic refrigerators) in a restricted area where only members of the research team will have access to them. Participants will have supplies provided to them in person every two-weeks and will be required to ingest two pots of Yakult, every day for six months. Participants will be instructed to ingest one 65ml pot in the morning (prior to breakfast) and one bottle in the evening (prior to an evening meal). They will also be instructed to avoid any other dietary supplement aimed at modulating the gut microbiota during the six month intervention period. Researchers will keep a log of the amount of pots supplied to participants and will visit the participants at the haemodialysis unit to supply more pots.

Placebo

The placebo will be indistinguishable (identical in taste and colour but will not contain Lactobacillus casei Shirota) to both participants and trial investigators. It will be stored and provided in exactly the same manner as the intervention product.

Compliance

A record of compliance for supplement ingestion will be completed by all participants (including days where they may have missed taking the supplement). Following feedback from a research patient group, all participants will be offered any or all of the following steps in any combination to aid adherence to the product:

• Phone call reminders (daily or weekly)

• Text or email alerts at any preferred schedule

• Regular visits / reminders in person on the dialysis units

Patient Numbers - Feasibility and Statistical Power Patients will be recruited from within the Leicester Renal Network, which includes ten dialysis units treating over 800 haemodialysis patients. The number of participants required is therefore readily attainable. Based on a previously reported (Wang et al., 2015), post-intervention change (compared to pre-intervention) in serum endotoxin following probiotic supplementation in peritoneal dialysis patients (-1.11 ± 1.5 EU/mL for probiotic and 0.86 ± 2.3 endotoxin units/mL for placebo), it was calculated (Stata IC version 15.1, StataCorp, Texa, USA) that n=44 (n=50 accounting for 10% dropout for death and transplantation over 6 months) was required to detect a significant difference between probiotic and placebo groups with 90% power and alpha 0.05.

Dropout rate A drop-out rate of 10% in line with previous studies is expected. This is also entirely in-keeping with previous experience of interventional studies in the haemodialysis population which show a 10-20% drop out rate due to death, transplantation and non-adherence (Graham-Brown et al., 2016).

Randomisation The trial design will be a randomised-controlled trial (RCT). Participants will be individually randomised to either the Lactobacillus casei Shirota or a well-matched placebo. After recruitment, participants will be randomised to one of two groups using the REDCap system by the bioinformatics team within the National Institute of Health Research Biomedical Research Centre at the University of Leicester.

Blinding This trial will be conducted in a double-blind manner. Both participants and researchers will be blind to the treatment allocation. Both the Lactobacillus casei Shirota (Yakult) and the placebo will be supplied, and simply marked as, 'A' or 'B', by Yakult Honsha. Neither the researchers nor the participants will know which is Yakult and which is placebo and will therefore both be unaware which product they are taking. Yakult Honsha will have no knowledge of which patients are randomised to which group. Once all patients have completed the study, the database has been locked and statistical analyses performed, the nature of the two product groups will be revealed by un-blinding.

Main assessments (at baseline and six months) will take place over one or more sessions dependent on patient preference. Blood and saliva samples will be taken at the start of dialysis, eliminating the need for additional venepuncture; relevant demographic data will be extracted from medical records throughout the trial and also collected from participants prior to their usual haemodialysis appointment. Participants will have the choice of completing the questionnaires during their usual haemodialysis appointment (with the assistance of a researcher) or taking them home to complete at their convenience and return them to the researcher at their next haemodialysis appointment. The questionnaires will take no longer than 30 minutes to complete.

Participants will have the choice of giving their faecal sample either at their normal dialysis appointment or will be given a kit to collect their sample at home. All data can be collected from participants around their usual haemodialysis treatment so as to reduce the additional time participants need to attend over and above their out-patient appointment. Although this may require them to arrive earlier (e.g. 30 minutes) than their usual appointment time.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 50
• Est. completion date: December 31, 2024
• Est. primary completion date: August 24, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Be a prevalent haemodialysis patient (>3 months)

2. Age 18 years or older

3. Able and willing to give informed consent

4. Sufficient understanding of English to understand the patient information sheet and complete questionnaires

Exclusion Criteria:

1. Aged <18 years

2. Unable or unwilling to give informed consent

3. Unlikely to remain on haemodialysis for the 6-month duration of the trial (e.g. planned transplantation)

4. Already taking a regular pre- or pro-biotic supplement or other dietary supplement aimed at modulating the gut microbiota

5. Any of the following conditions:

1. Documented allergy or intolerance to milk protein (e.g. lactose intolerance, milk/dairy allergy)

2. Autoimmune disease (e.g. systemic lupus erythematosus)

3. Inflammatory bowel disease (e.g. Crohn's colitis)

4. Diagnosed infectious illness within the previous 30-days

6. Prescribed any of the following medication:

1. Antibiotics or anti-viral medications within the previous 30-days

2. Steroids or other immunosuppressive agents -

Related Conditions & MeSH terms

• End Stage Renal Disease
• Kidney Failure, Chronic

Intervention

Dietary Supplement:
• Yakult
A fermented milk product with live microorganisms.
• Placebo
A milk product with no live microorganisms.

Locations

Country	Name	City	State
United Kingdom	University Hospitals of Leicester	Leicester	Leicestershire

Sponsors (6)

Lead Sponsor	Collaborator
University of Leicester	Chinese University of Hong Kong, Loughborough University, Universitaire Ziekenhuizen KU Leuven, Yakult Honsha Co., LTD, Yakult Honsha European Research Center, ESV

Country where clinical trial is conducted

United Kingdom, 

References & Publications (2)

Graham-Brown MP, March DS, Churchward DR, Young HM, Dungey M, Lloyd S, Brunskill NJ, Smith AC, McCann GP, Burton JO. Design and methods of CYCLE-HD: improving cardiovascular health in patients with end stage renal disease using a structured programme of exercise: a randomised control trial. BMC Nephrol. 2016 Jul 8;17(1):69. doi: 10.1186/s12882-016-0294-7. — View Citation

Wang IK, Wu YY, Yang YF, Ting IW, Lin CC, Yen TH, Chen JH, Wang CH, Huang CC, Lin HC. The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: a randomised, double-blind, placebo-controlled trial. Benef Microbes. 2015;6(4):423-30. doi: 10.3920/BM2014.0088. Epub 2015 Feb 12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of deaths (all causes)	Mortality	6 months
Other	Number of hospital admissions (all causes)		6 months
Other	Hospital length of stay (days)		6 months
Other	Number of active infections		6 months
Other	Supplement compliance as a percentage		6 months
Other	Food frequency questionnaire		Change at 6 months compared to baseline
Primary	Blood circulating endotoxin concentration	Gut derived toxic particle	6 months
Secondary	Blood circulating p-cresyl sulphate concentration	Translocated marker of cardiovascular risk	6 months
Secondary	Blood circulating indoxyl sulphate concentration	Translocated marker of cardiovascular risk	6 months
Secondary	Faecal bacterial load	Marker of altered microbiota	6 months
Secondary	Faecal bacterial diversity	Marker of altered microbiota	6 months
Secondary	Faecal ammonia concentration	Marker of altered microbiota	6 months
Secondary	Faecal indole concentration	Marker of altered microbiota	6 months
Secondary	Faecal phenol concentration	Marker of altered microbiota	6 months
Secondary	Faecal p-cresol concentration	Marker of altered microbiota	6 months
Secondary	Faecal calprotectin concentration	Marker of intestinal inflammation	6 months
Secondary	Faecal elastase concentration	Marker of intestinal inflammation	6 months
Secondary	Salivary immunoglobulin A concentration	Marker of mucosal immunity	6 months
Secondary	Salivary lysozyme concentration	Marker of mucosal immunity	6 months
Secondary	Blood circulating interleukin-6 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating interleukin-10 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating tumour necrosis factor alpha concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating high sensitivity c-reactive protein concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating interleukin-17 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating monocyte chemoattractant protein (MCP)-1 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating interleukin-8 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating RANTES concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating intercellular cell-adhesion molecule 1 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating vascular cell adhesion molecule 1 concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating E-selectin concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating P-selectin concentration	Marker of systemic inflammation	6 months
Secondary	Blood circulating C-terminal agrin fragment (CAF)	Marker of sarcopenia	6 months
Secondary	Blood circulating Irisin	Marker of sarcopenia	6 months
Secondary	Blood circulating Brain derived neurotrophic factor (BDNF)	Marker of sarcopenia	6 months
Secondary	Blood circulating MicroRNA's	Marker of sarcopenia	6 months
Secondary	Kidney disease quality of life instrument (KDQOL)	Quality of life questionnaire	6 months
Secondary	EQ-5D-5L	Quality of life questionnaire	6 months
Secondary	Gastrointestinal Symptom Rating Scale	Measure of gastrointestinal symptoms	6 months