Overview
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The Rifaximin in Dementia Trial (RIDE) is a Phase 1/2 clinical trial investigating the effects of rifaximin, a non-absorbable antibiotic, on patients with Alzheimer's disease (AD) and vascular dementia (VaD). This trial represents a novel approach targeting the gut-brain axis to potentially modify dementia progression["@nct"].
...Overview
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The Rifaximin in Dementia Trial (RIDE) is a Phase 1/2 clinical trial investigating the effects of rifaximin, a non-absorbable antibiotic, on patients with Alzheimer's disease (AD) and vascular dementia (VaD). This trial represents a novel approach targeting the gut-brain axis to potentially modify dementia progression["@nct"].
Rifaximin is a gut-targeted antibiotic that acts locally in the gastrointestinal tract with minimal systemic absorption. By modulating the gut microbiome, this trial tests the hypothesis that improving gut microbial function can reduce systemic inflammation and positively impact cognitive function in dementia patients.
Trial Details
| Attribute | Value |
|-----------|-------|
| NCT Number | [NCT06718686](https://clinicaltrials.gov/study/NCT06718686) |
| Phase | Phase 1/2 |
| Status | Recruiting |
| Enrollment | 20 patients (estimated) |
| Study Type | Interventional |
| Design | Sequential allocation, triple-blind (participant, care provider, outcomes assessor) |
| Start Date | December 30, 2024 |
| Primary Completion | December 2025 (estimated) |
| Completion | May 2026 (estimated) |
- Lead Sponsor: Jasmohan Bajaj, MD (Hunter Holmes McGuire VA Medical Center)
- Collaborator: Bausch Health Americas, Inc.
- Principal Investigator: Jasmohan Bajaj, MD (Richmond VA Medical Center)
Location
- Richmond VA Medical Center — Richmond, Virginia, United States
- Status: Currently recruiting
Study Hypothesis and Objectives
Hypothesis
Rifaximin SSD therapy is safe and well tolerated in patients with Alzheimer's disease and vascular dementia, with beneficial changes in systemic inflammation and biomarkers of dementia due to improvement in microbiota function compared to placebo.
Overall Objective
In a single-blind placebo-controlled trial in patients with Alzheimer's or vascular dementia, to determine the effect of rifaximin SSD compared to placebo on:
- Gut microbial structure and function
- Cognitive and daily function
- Caregiver burden
Mechanism of Action
Gut-Brain Axis Modulation
Rifaximin exerts its potential therapeutic effects through multiple mechanisms related to the [gut-brain axis](/mechanisms/gut-brain-axis):
1. Microbiome Modulation
- Selective antimicrobial action in the gut lumen
- Reduction of pathogenic bacterial overgrowth
- Preservation of beneficial gut bacteria
- Modulation of gut microbial diversity
2. Reduction of Systemic Inflammation
- Decreased gut-derived endotoxins (LPS)
- Reduced pro-inflammatory cytokines (IL-6, TNF-α, IL-1β)
- Increased anti-inflammatory cytokines (IL-10)
- Lower lipopolysaccharide-binding protein (LBP) levels
- Increased short-chain fatty acid (SCFA) production
- Modulation of bile acid metabolism
- Improved gut barrier function
4. Neuroprotective Effects
- Reduced neuroinflammation via decreased systemic inflammatory signals
- Potential reduction in amyloid-β burden
- Protection against tau pathology through decreased neuroinflammation
Why Rifaximin?
Rifaximin is an ideal candidate for gut-brain axis therapy because:
- Minimal systemic absorption: <1% systemic bioavailability
- Gut-selective action: Primarily acts in the gastrointestinal tract
- Good safety profile: Well-tolerated in previous clinical applications
- Broad-spectrum activity: Effective against gram-positive and gram-negative bacteria
- Low resistance development: Limited impact on gut bacterial resistance patterns
Study Design
Intervention Model
Sequential design where patients receive both placebo and active drug in a masked sequence.
Blinding
Triple-blind design where participants, care providers, and outcome assessors are masked to treatment assignment.
Treatment Arms
| Arm | Intervention |
|-----|---------------|
| Placebo | Placebo tablet BID |
| Rifaximin SSD 40mg IR BID | Rifaximin SSD 40 mg IR tablet BID |
Treatment Duration
10 weeks total (including both placebo and active treatment phases)
Eligibility Criteria
Inclusion Criteria
- Probable Alzheimer's Disease (AD) or Vascular Dementia (VaD) mild or moderate based on Clinical Dementia Rating Scale
- Males and Females Age ≥ 65 years
- Community living with availability of caregiver to accompany participant to study visits
- Able to consent or legal guardian who can consent (with participant assent)
- Legally authorized representative (LAR) and caregiver for the study is the same individual
- Fluency in written and spoken English (both participant and caregiver)
Exclusion Criteria
- Dementia not due to AD or VaD
- Clinically significant agitation or aggression (requiring antipsychotic medication)
- Delusions and/or hallucinations
- Severe psychopathology including major depression
- Unstable, severe, or poorly controlled medical conditions
- Visual and/or hearing disorder that prevents completion of neuropsychologic evaluations
- Diarrhea
- Hypersensitivity to rifaximin or any rifamycin antimicrobial agent
- Antibiotic use in the prior 6 months
- Taking medications that interact with Rifaximin (P-glycoprotein inhibitors require investigator discussion)
- History of alcohol and/or drug abuse
- Participation in another investigational drug trial in the last 30 days
Outcome Measures
Primary Outcomes
| Measure | Description | Time Frame |
|---------|-------------|------------|
| Change in stool and serum short-chain fatty acid levels | SCFA in stool and serum: rifaximin SSD phase vs placebo phase | 10 weeks |
| Change in bile acids in stool and serum | Bile acids: rifaximin SSD phase vs placebo phase | 10 weeks |
Secondary Outcomes
| Measure | Description | Time Frame |
|---------|-------------|------------|
| Systemic inflammatory change | Serum LBP, inflammatory cytokines (IL-6, TNF-α, IL-10, IL-1β) | 10 weeks |
| Stool microbiome composition | 16SrRNA microbiome composition and diversity | 10 weeks |
| Dementia biomarkers | Plasma Aβ42, Aβ40, Aβ42/40 ratio, p-tau181 | 10 weeks |
| MMSE | Change in Mini-Mental State Examination | 10 weeks |
| Cognitive testing (PHES) | Psychometric Hepatic Encephalopathy Score | 10 weeks |
| CDR-SB | Clinical Dementia Rating - Sum of Boxes | 10 weeks |
| EncephalApp Stroop performance | Off time and on time performance | 10 weeks |
| Critical flicker fusion analysis | CFF threshold | 10 weeks |
| Katz Index of Independence in ADL | Activity of Daily Living | 10 weeks |
| Lawton-Brody IADL | Instrumental Activities of Daily Living | 10 weeks |
| Zarit Burden Interview | Caregiver burden | 10 weeks |
| Sickness Impact profile | Quality of Life | 10 weeks |
| PROMIS-29 | Patient-Reported Outcomes Measurement Information System | 10 weeks |
| Safety | Serious adverse event rates | 10 weeks |
Clinical Relevance
Gut-Brain Axis in Dementia
This trial is significant because it directly tests the [gut-brain axis hypothesis in neurodegenerative diseases](/mechanisms/gut-brain-axis). Emerging evidence suggests that:
- Gut microbiome dysbiosis is associated with cognitive decline
- Systemic inflammation from gut sources may contribute to neuroinflammation
- Modulating the gut microbiome may offer a novel therapeutic approach
Biomarkers Being Studied
The trial includes comprehensive biomarker assessments:
- Amyloid-β: Aβ42/40 ratio (reduced ratio associated with cerebral amyloid)
- Tau: p-tau181 (marker of tau pathology and neuronal damage)
- Inflammatory markers: LBP, cytokines
- Microbiome markers: SCFAs, bile acids
Potential Impact
If successful, this trial could:
Establish gut microbiome modulation as a viable dementia therapeutic strategy
Identify responsive patient subgroups
Validate biomarker endpoints for future trials
Open new avenues for combination therapies targeting both gut and brainRelated Pages
- [Gut-Brain Axis in Neurodegeneration](/mechanisms/gut-brain-axis)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Exenatide Parkinson's Trial](/clinical-trials/exenatide-parkinsons) — Another gut-brain axis therapy trial
- [Valacyclovir HSV1 Parkinson's Trial](/clinical-trials/valacyclovir-hsv1-pd) — Antiviral approach to neurodegeneration
References
Unknown, NCT06718686: Rifaximin SSD in Dementia Trial (n.d.)