Pilot, Single Center, Open, Trial of Rifaximin in Probable Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Number of Participants Experiencing Diarrhea Caused by Clostridium Difficile
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •· 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
排除标准
- •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
研究组 & 干预措施
Rifaximin
rifaximin 550 milligrams (mg) orally twice daily for 3 months
干预措施: Rifaximin 550 milligrams (MG) (Drug)
结局指标
主要结局
Number of Participants Experiencing Diarrhea Caused by Clostridium Difficile
时间窗: 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.
Change in ADAS Cog 11 Scores
时间窗: 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.
次要结局
- Change in Cognitive Performance on the Mini-Mental State Exam (MMSE)(Baseline, 3 months)
- Participants With Treatment Emergent Adverse Events as Reported by the Subject That Required a Change in Safety Measures(Safety will be measured through adverse events throughout study, at month 3 and by phone call at month 5 (2 months after treatment termination).)
- Phosphorylated Tau(at baseline and at 3 months)
- Change in Neurofilament Light (Nfl) Levels(Baseline, 3 months)
- Change in Interleukin 1B (IL-1B)(Baseline, 3 months)
- Change in Interleukin 4 (IL-4)(Baseline, 3 months)
- Change in Tolerability as Measured by Number of Adverse Events (AE).(Baseline, 3 months, 5 months)
- Changes From Baseline in Ammonia Level(Baseline, 3 months)
- Change in Glial Fibrillary Acidic Protein (GFAP)(Baseline, 3 months)
- Change in Interleukin 10 (IL-10)(Baseline, 3 months)
- Changes in Interleukin 13 (IL-13) Following Treatment With Rifaximin(Baseline, 3 months)
- Change in Interleukin 2 (IL-2)(Baseline, 3 months)
- Change in Interleukin 5 (IL-5)(Baseline, 3 months)
- Change in Interleukin 8 (IL-8)(Baseline, 3 months)
- Change in Interleukin 6 (IL-6)(Baseline, 3 months)
- Change in Tumor Necrosis Factor a(Baseline, 3 months)
- Development of Clostridium Difficile Diarrhea(Baseline to 3 months)
- Total Tau(Baseline, 3 months)