Changes in Microbiota and Metabolomic Profile Between Rifaximin Responders and Non-responders In Diarrhoea-Predominant Irritable Bowel Syndrome

Irritable Bowel Syndrome With Diarrhea Clinical Trial

Official title: Changes in Microbiota and Metabolomic Profile Between Rifaximin Responders and Non-responders In Diarrhoea-Predominant Irritable Bowel Syndrome

Status Completed

Clinical Trial Summary

Irritable Bowel Syndrome (IBS) carries a high prevalence worldwide and imposes substantial economic burden on patients, healthcare systems and society. In recent years, dysbiosis of the gut microbiota and bile acid (BA) malabsorption have been identified as putative pathophysiological mechanisms. Bile acid metabolism and gut microbiota are closely related. When patients with IBS-D were compared to healthy subjects, total levels of faecal BAs do not differ, but increased faecal primary BAs and reduced secondary BAs have been repeatedly observed in patients with IBS-D, suggesting abnormal BA deconjugation. Rifaximin, a non-absorbable antibiotic, has been shown in a recent meta-analysis to produce a therapeutic clinical gain compared to other treatment options for IBS, including placebo, paralleled by a high safety profile. It is also now known that changes in fecal microbiota have been observed in patients with IBS who have responded positively to Rifaximin. The relationship between microbiota changes, metabolomics changes after Rifaximin is unclear. There is emerging data to suggest duodenal dysbiosis as a putative pathophysiology, which in one study, clustered together with salivary microbiota than with fecal microbiota. However, the oral microbiome in patients with IBS has never been explored, which could possibly explain the downstream observations of duodenal and fecal dysbiosis. The investigators aim to assess the changes in metabolomic and microbiota profile after Rifaximin treatment, between responders and non-responders. The investigators will also explore the oral microbiome in IBS patients, and assess its relationship with fecal microbiome between responders and non-responders.

Clinical Trial Description

The primary hypothesis of the study is that amongst responders to Rifaximin, fecal primary BAs will be significantly reduced, and faecal secondary BAs significantly increased after treatment.

The secondary hypotheses include:

1. Reduction in Escherichia and increase in Lactobacillus after treatment, as a possible mechanism to explain the increased deconjugation of primary BAs observed.

2. Oral microbiome correlates with gut microbiome dysbiosis in IBS-D subjects.

3. Rifaximin therapy alters both oral and gut microbiota, and that responders to Rifaximin harbour different microbiota compared to non-responders.

1. Primary Objectives Primary Objective: To compare oral microbiome and fecal microbiome in IBS-D patients before and after Rifaximin, examining differences between responders and non-responders.

2. Secondary Objectives Secondary objectives: To examine the differences between stool and salivary metabolomics, urinary metabolomics and serum immunomics and metabolomics, between responders and non-responders to Rifaximin in IBS-D subjects.

Responders to Rifaximin will be defined as patients having a 50 point or more reduction in the IBS Symptom Severity Score (IBS-SSS) after treatment. This indicates that the patient has experienced a significant improvement in the reduction of symptoms. The IBS-SSS is a well-validated questionnaire that is patient-administered. This questionnaire will be administered at Day 0 and Day 14 of Rifaximin.

Up to 50 subjects with Diarrhoea-predominant Irritable Bowel Syndrome (IBS-D) will be recruited from the National University Hospital Gastroenterology clinic and Singapore General Hospital Gastroenterology clinic. There will be subject restrictions on race, so as to limit variation due to inter-racial differences and ensure homogeneity in the subject population.

Determination of Sample Size Adopted from the sample size calculation table for human microbiome studies by La Rosa (La Rosa et al. 2012), the study will require 15 subjects to have 80% power at p<0.05 significance level. To account for multiple testing, investigators will require at least 25 subjects for each category to have 90% power at p<0.01 significance level. The investigating team will be recruiting a total of 40 respondents and 40 non-respondents from both NUH and SGH.

Statistical and Analytical Plans Pair-wise comparison will be conducted between the 2 sample groups for differences in the microbiome. Concordance will be examined between the oral and fecal groups, both before and after treatment. Identified species will be examined for possible metabolic pathways based on their genetic profiles generated by the metagenomic analysis.

Data Quality Assurance Demographics will be collected from the patient medical records. The oral conditions will be recorded in data collection form after oral examinations. The data collection form will be checked and signed off by PI. All the records will be entered twice into database by the delegated study team members to ensure accuracy of data.

Data Entry and Storage Initial collection will be on paper-based data collection form. All subjects will be assigned a unique study subject code and the data collection form will be labelled with subject recruitment number. The de-identified data will be transferred into analysis software and kept on an encrypted flash drive kept by the delegated study team members. The data collection form will be put in lockable cabinet for 6 years after study completion, being accessed by study team only. De-identified data may be provided to a biostatistician for further analysis.

Study Visits and Procedures This is a multi-centre open-label prospective cohort study. Recruited subjects will be patients who are newly diagnosed IBS-D, who undergo a two-week course of Rifaximin as indicated by their primary physician. Patients with symptomatic improvement (responders) after treatment will be compared to patients who do not improve (non-responders), based on a validated IBS Symptom Severity Score. As this is a cohort study, there will be no randomization or blinding. All patients will receive Rifaximin and no placebo will be used.

The study will consist of the following phases:

Visit 1: Screening The screening phase will include assessing eligibility based on the inclusion and exclusion criteria, obtaining informed consent, followed by a one-week symptom, bowel and 3-day dietary diary. All subjects will undergo further oral examination to determine oral status such as caries and periodontal status. This is to accurately evaluate the patient's baseline symptoms, bowel and dietary habits. Patients will be given a stool collection kit for collection of stool sample (10-20g) to be returned before or at the next visit.

Visit 2: Enrolment and treatment (Day 1 Rifaximin) After the screening phase, patients will complete the IBS-SSS, and will be enrolled if a score of 300 or greater is obtained. Urine (50ml), saliva (5-10ml), 2 buccal swabs and blood samples (20ml) will be obtained during this visit as well.

Patients will then initiate Rifaximin for two weeks. During these two weeks, patients will continue the symptom, bowel and 3-day dietary dairy, and also whether they have remembered to take their medication, and any side effects observed.

Visit 3: Follow-up post-treatment (Day 14 Rifaximin) Patients will be asked to provide stool (10-20g), urine (50ml), saliva (5-10ml), 2 buccal swabs and blood samples (20ml) again at or 1-week after Day 14, and repeat the IBS-SSS. The diaries will be collected, and compliance to medication will be verified.

Subjects who discontinue the study early due to an AE will be followed until resolution or stabilization of the event.

Visit 4: Review of symptoms 90 days after completing Rifaximin treatment. Patients will be asked to repeat the IBS-SSS. The symptom, bowel and 3-day dietary dairy will be collected and patients will be asked to provide stool (10-20g), urine (50ml), saliva (5-10ml), 2 buccal swabs and blood samples (20ml). ;

Related Conditions & MeSH terms

• Diarrhea
• Irritable Bowel Syndrome
• Irritable Bowel Syndrome With Diarrhea
• Syndrome

• NCT number: NCT03557788
• Study type: Interventional
• Source: National University Hospital, Singapore
• Status: Completed
• Phase: Phase 4
• Start date: May 7, 2018
• Completion date: August 13, 2021