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Trial of Rifaximin in Probable Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT03856359
Recruitment Status : Recruiting
First Posted : February 27, 2019
Last Update Posted : April 11, 2019
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

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
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
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021

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. Change in Alzheimer's Disease Assessment Scale - Cognitive (ADAS-COG) [ Time Frame: Change from baseline global cognitive scores at month 3. Global cognitive performance assessed by a psychometrician using (ADAS-Cog). ]
    Done at Baseline, 3 month and 5 month visits. ADAS-Cog is a widely used cognitive endpoint in AD clinical trials and changes on this scale, over time, are considered clinically meaningful. ADAS-11 range is 0-70 with higher scores indicating worse performance. Errors from 11 items are added to generate the total score.

  2. Occurrence of Adverse Events [ 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.


Secondary Outcome Measures :
  1. Change in Serum neuronal markers [ Time Frame: Baseline, 3 months ]
    Done at Baseline, 3 month and 5 month visits. When brain tissue is damaged, it releases substances (serum neuronal markers) into the blood, such as Neurofilament Light. The investigators will be looking for the amount of these serum neuronal markers to decrease after three months of Rifaximin treatment, indicating less brain tissue damage.

  2. Change in Serum pro-inflammatory markers [ Time Frame: Baseline, 3 months ]

    The investigators will be looking for changes in the amounts of the following pro-inflammatory markers:

    Interleukin (IL) 1 beta, IL 2, IL 4, IL 5, IL 6, IL 8, IL 10, IL 13, Tumor necrosis factor - alpha


  3. Change in gut microbiota [ Time Frame: Baseline, 3 months ]
    The study drug, Rifaximin, is an antibiotic. It changes the mixture of bacteria in the colon. The investigators will analyze the types of bacteria that are in the patient's colon. The microbiome variables the investigators will use standard FDR correction to examine nominal significance of change from baseline. The investigators will be assessing the Escherichia, shigella, pseudomonas, bacteroides, eubacterium and Faecalibacterium.

  4. 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.

  5. Change in cognitive performance on the Mini-Mental State Exam (MMSE) [ Time Frame: Assessed at screening and month 3 ]
    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.

  6. Changes in Safety measures as measured by treatment emergent AEs as reported by the subject [ 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). ]
    Safety will be measured through adverse events as reported by the subjects

  7. Changes in Complete Blood Count (CBC) [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from the baseline on CBC will be considered an AE and clinically significant

  8. Changes in blood pressure [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from baseline to month 3 in blood pressure.

  9. Changes in pulse [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from baseline to month 3 in pulse.

  10. Changes in Chemistry values [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from the baseline on Chemistry values as defined as Creatine, blood urine nitrogen, electrolytes and sodium potassium chloride results will be considered an AE.

  11. Changes in Liver Function Test (LFT) will be measured by ALT and AST lab results from baseline [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from the baseline on LFT will be considered an AE.

  12. Changes in C Difficile infection [ Time Frame: Safety will be measured through labs at screening and at month 3. ]
    Clinically significant deviations from the baseline on clinically significant and newly emergent C Difficile infection will be considered.



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


Contacts
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Contact: Mark A Mayo, BA 919-684-7752 mark.mayo@duke.edu
Contact: Paul Suhocki, MD 919-684-7284 paul.suhocki@duke.edu

Locations
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United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Mark Mayo, BA    919-684-7752    mark.mayo@duke.edu   
Contact: Paul Suhocki, MD    919-684-7284    paul.suhocki@duke.edu   
Principal Investigator: Paul Suhocki, MD         
Sub-Investigator: Pudugramam Doraiswamy, MD         
Sponsors and Collaborators
Duke University
Bausch Health Americas, Inc.
Investigators
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Principal Investigator: Paul Suhocki, MD Duke University

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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT03856359     History of Changes
Other Study ID Numbers: Pro00093318
First Posted: February 27, 2019    Key Record Dates
Last Update Posted: April 11, 2019
Last Verified: April 2019
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