Trial of Rifaximin in Probable Alzheimer's Disease
Condition: Alzheimer's Disease
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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 altering gut microbiota and lowering blood ammonia
      levels. It is FDA approved for use in patients with hepatic encephalopathy. Rifaximin lowers
      blood ammonia by blocking gut bacterial RNA synthesis and also by increasing small bowel
      glutaminase. The Investigators hypothesize that rifaximin will improve cognition and function
      in AD patients by mechanisms such as lowering circulatory pro-inflammatory cytokines secreted
      by harmful gut bacteria or lowering blood ammonia.

      Rifaximin is a relatively gut-specific antibiotic that interferes with by binding to the
      transcription subunit of bacterial . Because Rifaximin is absorbed poorly, most of the drug
      taken RNA polymerase orally stays in the gastrointestinal tract. It has been available since
      2004 in the US and has orphan gastrointestinal tract drug status for hepatic encepalopathy.
      Rifaximin's relatively good safety profile and its ability to alter gut flora and lower blood
      ammonia have made it an attractive drug to treat hepatic encephalopathy or conditions such as
      traveller's diarrhea. The Investigators hypothesize that rifaximin will improve cognition and
      function in AD patients by mechanisms such as lowering circulatory pro-inflammatory cytokines
      secreted by harmful gut bacteria or lowering blood ammonia.

      The Investigators will measure a variety of blood markers, such as pro-inflammatory and
      anti-inflammatory compounds, and analyze fecal microbiota in patients with AD before and
      after 3 months of rifaximin therapy. If patients exhibit measurable improvement in cognition
      and function, The Investigators will analyze our data to see if their improvement correlates
      with a shift towards anti-inflammatory species in the gut and a similar shift in the blood
      cytokine panel to favoring anti-inflammatory compounds.

      Evidence supporting our hypothesis for this study is presented below.

      Gut Microbiota Dysbiosis

      The gut harbors 95% of the total human microbiome and is made up of more than 5,000 taxa. Gut
      species remain relatively constant throughout adulthood until the seventh decade, when it
      becomes less diverse, harboring higher numbers of Proteobacteria and lower numbers of
      Bifidobacteria. An imbalance in the gut bacterial species can weaken the intestinal barrier
      and create system wide inflammation via gut lymphoid tissue which comprises 70% - 80% of the
      immune system. Blood brain barrier permeability is also altered. The gut bacteria secrete
      pro-inflammatory compounds and neuroactive molecules that include serotonin,
      gamma-aminobutyric acid (GABA), catecholamines and acetylcholine which cross the blood brain
      barrier and cause brain inflammation and brain dysfunction.

      A growing number of pro-inflammatory compounds secreted by gut bacteria and seen in patients
      with AD are being discovered. These include interleukin (IL) - 6, tumor necrosis - alpha and
      the inflammasome complex (NLRP3). A recent study revealed higher numbers of Escherichia and
      Shigella in the gut of amyloid positive AD patients when compared with healthy controls and
      this correlated with higher levels of circulating pro-inflammatory cytokines. The AD patients
      also had lower numbers of gut Eubacterium rectale and this correlated with lower levels of
      circulating anti-inflammatory compounds than seen in controls. Other researchers found that a
      preponderance of gut Bacteroides and Blautia and reduced numbers of SMB53 and Dialister
      correlated with elevated levels of brain amyloid Cerebrospinal Fluid (CSF) biomarkers.
      Interestingly, Clostridium tyrobutyricum and Bacteroides thetaiotaomicron, have been shown to
      actually increase the integrity of the blood brain barrier by enhancing expression of tight
      junction proteins and helping to maintain brain homeostasis. Recent evidence also suggests
      that neurotransmitters and neuropeptides secreted by bacteria in the gut activate vagal nerve
      ascending fibers, influencing brain function.

      Ammonia Neurotoxicity

      A second theory is that the blood brain barrier allows greater amounts of ammonia into the AD
      brain, triggering or worsening pre-existent changes. The possibility that ammonia is at least
      partly responsible for the pathologic changes seen in the AD brain was first proposed by
      Seiler in 1993, when he noted that some of the changes in the AD brain can also be seen in
      the brains of hyperammonemic patients. Arteriovenous sampling in early stage normoammonemic
      AD patients demonstrated higher endogenous cortical ammonia compared to young control
      subjects Low glutamine synthetase levels have been found to correlate with increased density
      of amyloid deposits in the AD brain.

      The brain also receives exogenous ammonia, of which the gut is a major source. The aging
      colon contains a greater percentage of protein fermenting bacteria than is seen in the colon
      of younger patients.

      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 circulatory pro-inflammatory cytokines secreted by harmful gut bacteria
      and / or lowering blood ammonia levels. 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-Cog11 will be
      administered at baseline and at the 3 month endpoint. Interim safety checks will occur via
      phone calls one week after baseline and then every 2 weeks till 3 month end point. Serum
      neuronal biomarkers, ammonia levels and pro-inflammatory and antiinflammatory 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.

      This is an open label pilot study designed to provide preliminary evidence on the clinical
      efficacy of rifaximin in improving cognition in AD patients. The Investigators will be
      looking for improvement in test scores and changes in serum levels of neuronal markers,
      circulating cytokine pro-inflammatory compounds and colonic microbiota following treatment.
      The Investigators will also be collecting data regarding the safety of long term use of this
      non-absorbed antibiotic for this disease. This pilot may form the basis for a future larger
      randomized, double blind controlled study to further test this hypothesis.

      The rifaximin dosage and route of administration are the same as that used to treat hepatic
      encephalopathy, for which the drug and dosage are FDA approved. The dose will remain the same
      throughout the 3 month study of rifaximin administration unless stopped for safety reasons.
      The age and study sample of mild to moderate probable AD is similar to that used in AD prior
      trials. The Investigators will select our sample to be medically stable and free of hepatic
      disease and not having had recent antibiotic therapy to minimize risk for C Difficile
      infection.

      The end of the study will occur 5 months after baseline testing and first administration of
      the drug. While drug administration will conclude and endpoint testing will be done at 3
      months, The Investigators will continue to follow each subject for an additional 2 months, as
      C. difficile infectious diarrhea can occur up until 2 months after stopping an antibiotic.
    

Intervention name(s): Rifaximin 550 milligrams (MG)
Intervention type(s): Drug
Intervention description(s): 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.
Intervention MeSH terms: Rifaximin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment