Gut Microbiome and p-Inulin in Hemodialysis

Study Overview
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Brief Summary
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The Microbiome trial is a non-randomized, open-label, sequential, multi-center study of p-inulin for patients with hemodialysis-dependent end-stage renal disease.

Detailed Description
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This primary objective of this exploratory study is to characterize the safety and tolerability of p-inulin (Prebiotin®, provided by JGI Medical) in altering the composition and function of the human gut microbiome, thereby reducing the generation of gut-derived uremic toxins, improving gut barrier function and attenuating systemic inflammation in patients treated with maintenance hemodialysis. The study also aims to assess the feasibility of conducting a full-scale trial of p-inulin. The primary efficacy parameters of the trial will be intra- and inter-participant variability in gut metabolites and bacterial composition. Secondary parameters of interest include tolerability and safety of p-inulin, willingness of hemodialysis patients to enroll in a study requiring repeated collection of stool samples, and participant adherence to agent treatment and specimen collection schedules.

Official Title
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A Multi-center Study to Characterize the Gut Microbiome of Individuals With End-stage Renal Disease Treated With Maintenance Hemodialysis, and to Explore Effects of P-inulin on the Gut Microbiome

Conditions
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End-Stage Renal Disease, Gut Microbiome Dysbiosis

Intervention / Treatment
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* Dietary Supplement: p-inulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Maintenance hemodialysis therapy for end-stage renal disease At least 18 years of age At least 90 days since hemodialysis initiation Self-reported average stool frequency of at least 1 every other day For women of childbearing potential, willingness to use a highly effective method of birth control for up to 4 weeks after the last dose of p-inulin. Ability to provide consent Exclusion Criteria: Use of prebiotics or probiotics during the past 8 weeks Consumption of probiotic yogurt during the past 2 weeks Use of antibiotics within the past 8 weeks Presence of HIV infection, chronic wound infection, osteomyelitis, or current hemodialysis Inflammatory bowel disease, chronic diarrhea, current C. difficile infection Cirrhosis or chronic active hepatitis Anticipated kidney transplantation, change to peritoneal dialysis, or transfer to another dialysis unit within 9 months Expected survival less than 9 months Pregnancy, anticipated pregnancy, or breastfeeding Incarceration Participation in another intervention study Severe anemia defined as hemoglobin <9.0 g/dl within the past 4 weeks as documented in the dialysis unit patient record

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Sequential Assignment
Interventional Model Description: This is a sequential trial that included three sequential phases: 1. Pre-treatment phase: 8 weeks during which no treatment was administered 2. p-Inulin phase: 12 weeks during which p-inulin was administered 8g orally twice daily 3. Post-treatment phase: 8 weeks during which no treatment was administered. Eleven of the 13 participants in the p-inulin phase entered the post-treatment phase. The other two withdrew prior to the post-treatment phase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single arm<br>This is a sequential study in which participants are observed (no intervention) for 8 weeks (pre-treatment), then participants self-administer p-inulin 8g orally twice daily for 12 weeks (treatment phase), and then observed for a final 8 weeks during which no treatment was administered (post-treatment). | Dietary Supplement: p-inulin<br>* 12 week self-administered treatment phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Within Participant Variability in Microbiome Composition by Treatment Phase | The weighted UniFrac distance was used to compute the distances for each sample. Weighted UniFrac distance uses species abundance information and weights the branch length with abundance difference. Weighted UniFrac distance is most sensitive to detect change in abundant lineages since it uses absolute abundance difference in its definition. | 28 weeks | 
| Within Participant Variability in Stool Metabolome by Treatment Phase | The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms. | 28 weeks | 
| Within Participant Variability in Plasma Metabolome by Treatment Phase | The Euclidean distance was used to compute the distances for each sample. The Euclidean distance is defined as the distance between two points. Differences between samples were determined on the basis of distances from the initial measurements to account for participant-level differences in initial abundance of microorganisms. | 28 weeks (8 weeks pre-treatment, 12 weeks of treatment, 8 weeks post-treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Score of Gastrointestinal Symptom Rating Scale (GSRS) (Safety Outcome) | Gastrointestinal symptoms as measure by the Gastrointestinal Symptom Rating Scale (GSRS). The GSRS total score is the sum of 15 0-3 items where 0 indicates absence and 3 an extreme degree of the symptom. A higher score indicates worse outcome. The minimum score is 0, the maximum score is 45. | GSRS was assessed at Weeks 0, 4, 8, 12, 16, 20, 24 and 28. | 
| Number of Participants Who Discontinued Use of P-inulin (Tolerability Outcome) | -Early discontinuation of p-inulin | 12 weeks | 
| Number of Participants Who Reduce the Dose of P-inulin (Tolerability Outcome) | -Reduction in p-inulin dose | 12 weeks | 
| Number of Participants With Adverse Events (Safety Outcome) | -Adverse events per participant related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System | 28 weeks | 
| Number of Serious Adverse Events (Safety Outcome) | Serious adverse events categorized by body systems, related to treatment as coded using the Medical Dictionary for Regulatory Activities (MedDRA) Coding System | 28 weeks | 
| Rate of Enrollment Refusal (Feasibility Outcome) | Enrollment refusal rate | 1 year | 
| Stool Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | Percent of expected completed protocol-specified stool sample collections | 28 weeks | 
| Blood Specimen Collection Proportion - Protocol Adherence (Feasibility Outcome) | Proportion of completed blood sample collections | 28 weeks | 
| Adherence Rate of P-inulin Use (Feasibility Outcome) | Proportion of p-inulin packets used | 12 weeks | 
| Rate of Study Withdrawal (Feasibility Outcome) | Number of withdrawals during each phase of the study | 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hemodialysis, p-inulin, gut microbiome