Rifaximin SSD in Dementia Trial (RIDE)

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

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

Sponsors and Collaborators

• 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:

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

3. Metabolite Production

• 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

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

Secondary Outcomes

Clinical Relevance

Gut-Brain Axis in Dementia

This trial is significant because it directly tests the gut-brain axis hypothesis in neurodegenerative diseases. 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:

1. Establish gut microbiome modulation as a viable dementia therapeutic strategy

2. Identify responsive patient subgroups

3. Validate biomarker endpoints for future trials

4. Open new avenues for combination therapies targeting both gut and brain

Related Pages

• Gut-Brain Axis in Neurodegeneration

• Alzheimer’s Disease

• Exenatide Parkinson’s Trial — Another gut-brain axis therapy trial

• Valacyclovir HSV1 Parkinson’s Trial — Antiviral approach to neurodegeneration