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Trial of Rifaximin in Probable Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03856359
Recruitment Status : Completed
First Posted : February 27, 2019
Results First Posted : December 17, 2021
Last Update Posted : December 17, 2021
Sponsor:
Collaborator:
Bausch Health Americas, Inc.
Information provided by (Responsible Party):
Duke University

Brief Summary:

This study aims to improve cognition and function in patients with Alzheimer's Disease (AD) by administering the oral antibiotic, Rifaximin.

Rifaximin is a virtually non-absorbed antibiotic with the unique properties of lowering blood ammonia levels and altering gut microbiota. It is FDA approved for use in patients with hepatic encephalopathy. Rifaximin lowers blood ammonia by altering fecal flora by blocking bacterial RNA synthesis and also by increasing small bowel glutaminase. The Investigators hypothesize that rifaximin will improve cognition and function in AD patients by lowering blood ammonia and / or lowering circulatory pro-inflammatory cytokines secreted by harmful gut bacteria. The Investigators will enroll up to 10 subjects with probable middle stage Alzheimer's Disease. The subjects will be given rifaximin 550 mg orally twice daily for 3 months after evaluation to ensure they have no contraindications. Physician clinical and safety assessments, adverse events, as well as the ADAS-Cog-11 will be administered at baseline and at the 3 month endpoint and two months after stopping treatment (at month 5). Interim safety checks will occur via phone calls one week after baseline and then every 2 weeks till end point. Serum neuronal biomarkers, ammonia levels and pro-inflammatory and anti-inflammatory compounds will also be measured at those times. Bodily fluids (Stool samples) will also be collected. Because of a small risk of developing C. difficile up to 2 months following the last administration of rifaximin, the subjects will be followed for an additional 2 months after the 3 month treatment ends.

Rifaximin is contraindicated in patients with hypersensitivity to rifaximin or rifamycin antimicrobials. Hypersensitivity reactions include exfoliative dermatitis, angioneurotic edema, and anaphylaxis. Clostridium difficile associated diarrhea is a risk whenever a patient is maintained chronically on antibiotics, with complications ranging from mild diarrhea to fatal colitis. Drug resistant bacteria can also result from long term use. There is increased systemic exposure to rifaximin in patients with severe hepatic impairment or in patients who are taking P-glycoprotein inhibitors concomitantly. Regarding use in geriatric patients, there were no reported overall differences in the safety of the drug when used in patients 65 years of age or over, when compared with younger subjects.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Rifaximin 550 milligrams (MG) Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot, Single Center, Open, Trial of Rifaximin in Probable Alzheimer's Disease
Actual Study Start Date : April 9, 2019
Actual Primary Completion Date : November 19, 2020
Actual Study Completion Date : November 19, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Rifaximin

Arm Intervention/treatment
Experimental: Rifaximin
rifaximin 550 milligrams (mg) orally twice daily for 3 months
Drug: Rifaximin 550 milligrams (MG)
Rifaximin (Xifaxan, Salix Pharmaceuticals, Bridgewater, N.J.) (See Package Insert) is a drug that is approved by the FDA for use in humans for the treatment of Hepatic Encephalopathy, Traveler's Diarrhea and Irritable Bowel Syndrome. It is commercially available. It will be used in accordance with approved labeling as pertains to dosage and administration for Hepatic Encephalopathy, contraindications and warnings. However, it will be used investigationally in this trial as rifaximin is not FDA approved for the treatment of Alzheimer's Disease.




Primary Outcome Measures :
  1. Number of Participants Experiencing Diarrhea Caused by Clostridium Difficile [ Time Frame: 5 months ]
    Collected at every visit and follow-up phone visits. A rare side effect of Rifaximin is diarrhea caused by clostridium difficile. This is a very serious form of diarrhea that can be fatal if not treated. The investigators will be following the patients closely during treatment and for 2 months following treatment to see if the patient has any signs or symptoms of this diarrhea. If a patient does develop clostridium difficile diarrhea, they will be promptly treated.

  2. Change in ADAS Cog 11 Scores [ Time Frame: At baseline and at 3 months ]
    Change in Alzheimer's Disease Assessment Scale - Cognition test with 11 tasks (ADAS Cog 11) scores following 3 months of oral Rifaximin. Scores range from minimum 0 - maximum 70. Higher scores mean worse outcome.


Secondary Outcome Measures :
  1. Change in Tolerability as Measured by Number of Adverse Events (AE). [ Time Frame: Baseline, 3 months, 5 months ]
    Assessed at every visit. The patients will be followed closely to see if they are tolerating the drug, Rifaximin. The of the number of side effects would indicate that the patient may not be tolerating the drug. Most of these side effects are minor and include headache, nausea, vomiting, tiredness. A potentially fatal side effect would be the development of clostridium difficile diarrhea. The investigators will be following the patients closely during treatment and for 2 months following treatment to see if the patient has any signs or symptoms of this diarrhea. If a patient does develop clostridium difficile diarrhea, they will be promptly treated.

  2. Change in Cognitive Performance on the Mini-Mental State Exam (MMSE) [ Time Frame: Baseline, 3 months ]
    Change from baseline global cognitive scores at month 3). Global cognitive performance will be assessed by a psychometrician using the (MMSE). It is a brief cognitive questionnaire with a maximum score of 30 points. MMSE range is 0-30 with lower scores indicating worse performance. The number of correct answers is added to generate the total score.

  3. Participants With Treatment Emergent Adverse Events as Reported by the Subject That Required a Change in Safety Measures [ Time Frame: Safety will be measured through adverse events throughout study, at month 3 and by phone call at month 5 (2 months after treatment termination). ]
    Emergent AEs that required a change in safety measures. These were AEs that were found when talking to or examining the subjects.

  4. Changes From Baseline in Ammonia Level [ Time Frame: Baseline, 3 months ]
    Change in ammonia levels following treatment with Rifaximin.

  5. Development of Clostridium Difficile Diarrhea [ Time Frame: Baseline to 3 months ]
    Observing for development of diarrhea due to Clostridium difficile

  6. Total Tau [ Time Frame: Baseline, 3 months ]
    Change in serum Total tau after 3 months Rifaximin administration.

  7. Phosphorylated Tau [ Time Frame: at baseline and at 3 months ]
    Change in Phosphorylated tau following 3 months oral Rifaximin

  8. Change in Glial Fibrillary Acidic Protein (GFAP) [ Time Frame: Baseline, 3 months ]
    Change in Glial Fibrillary Acidic Protein (GFAP) after 3 months of oral Rifaximin

  9. Change in Neurofilament Light (Nfl) Levels [ Time Frame: Baseline, 3 months ]
    Change in Neurofilament Light levels after Rifaximin for 3 months

  10. Change in Interleukin 10 (IL-10) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 10 following 3 months Rifaximin

  11. Changes in Interleukin 13 (IL-13) Following Treatment With Rifaximin [ Time Frame: Baseline, 3 months ]
    Interleukin 13 levels after Rifaximin

  12. Change in Interleukin 1B (IL-1B) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 1B following Rifaximin

  13. Change in Interleukin 2 (IL-2) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 2 following Rifaximin

  14. Change in Interleukin 4 (IL-4) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 4 after Rifaximin

  15. Change in Interleukin 5 (IL-5) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 5 after Rifaximin

  16. Change in Interleukin 8 (IL-8) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 8 after Rifaximin

  17. Change in Interleukin 6 (IL-6) [ Time Frame: Baseline, 3 months ]
    Change in Interleukin 6 following Rifaximin

  18. Change in Tumor Necrosis Factor a [ Time Frame: Baseline, 3 months ]
    Change in Tumor Necrosis Factor a



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   55 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • · Probable Alzheimer's Disease (National Institute of Neurological Disorders and Stroke (NINDS) criteria), mild to moderate severity

    • Ages 55-85; both genders
    • Mini Mental State Exam (MMSE) scores 10-23
    • Willing and able to comply with all scheduled clinic visits.
    • Stable medical health
    • Has a family or professional caregiver who has regular contact with subject
    • Ability to consent or legal guardian who can consent
    • Living at home or in a facility
    • On no AD therapies or on stable (2 months) concurrent AD therapies

Exclusion Criteria:

  • Past history of C diff infection
  • Assessment, laboratory examination, physical examination or any other medical condition or circumstance making the volunteer unsuitable for participation in the study in the judgment of the study clinicians
  • Allergy to Rifaximin
  • Antibiotic use or hospitalization in the last 6 months
  • Are taking medications that interact with rifaximin and/or pose a safety risk in the judgment of the PI
  • Clinically significant abnormal hepatic or renal function
  • Uncorrected thyroid or B12 abnormalities
  • Participation in another investigational drug trial in the past 30 days
  • History of febrile illness within 5 days prior to the study period
  • Known Hyperammonemia caused by:

Valproic acid Chemotherapy Lung transplant Bariatric surgery Ureterosigmoidoscopy Hyperalimentation Urinary tract infection Errors of metabolism: urea cycle, enzyme deficiencies, organic acidemias, fatty acid oxidation, amino acid transport defects


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03856359


Locations
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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Duke University
Bausch Health Americas, Inc.
Investigators
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Principal Investigator: Paul Suhocki, MD Duke University
  Study Documents (Full-Text)

Documents provided by Duke University:
Study Protocol  [PDF] September 6, 2019
Statistical Analysis Plan  [PDF] September 6, 2019
Informed Consent Form  [PDF] December 9, 2019

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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT03856359    
Other Study ID Numbers: Pro00093318
First Posted: February 27, 2019    Key Record Dates
Results First Posted: December 17, 2021
Last Update Posted: December 17, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Rifaximin
Anti-Bacterial Agents
Anti-Infective Agents
Gastrointestinal Agents