A Placebo Controlled Single Centre Double Blind Randomised Trial to Investigate the Efficacy of Rifaximin Versus Placebo in Improving Systemic Inflammation and Neutrophil Malfunction in Patients With Cirrhosis and Chronic Hepatic Encephalopathy
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 38
- 试验地点
- 1
- 主要终点
- Rifaximin-α reducing neutrophil spontaneous oxidative burst ex vivo
研究概览
简要总结
Patients with cirrhosis are particularly prone to infection which is frequently a precipitant of hepatic encephalopathy, renal failure and circulatory collapse. Bacterial infections are of particular concern in patients with cirrhosis because they are poorly tolerated. Sepsis and associated endotoxaemia whereby bacteria produce inflammatory particles occur in approximately 40% of hospitalized patients with cirrhosis and is a major cause of death.
Gut-derived and blood-borne pathogens can induce an inflammatory response within the liver and spleen, which are the major organs that remove bacteria and their endotoxin (such as lipopolysaccharide - LPS and bacterial DNA itself) from the bloodstream. Several mechanisms have been identified and proposed in this process which depends upon a balance between the barrier functions of the gut and the 'detoxifying' capacity of the liver. People with established liver cirrhosis have been shown to have escape of endotoxin into the bloodstream produced by bacteria that reside in their intestines, which becomes more permeable or 'leaky'.
Gut dysfunction is defined by changes in the types of bacteria within the gut and in overall permeability allowing bacterial products which would otherwise be contained within the gut to travel into the bloodstream and lymphatic system with detrimental effects elsewhere in the body. This passage of bacterial products is termed bacterial translocation, and it's effects on the liver and general immune system can be then be measured.
It has now become recognised that certain types of white blood cells such as neutrophils and monocytes become dysfunctional and this predisposes to infection and may also have a more direct pathogenic role in hepatic encephalopathy. Thus neutrophil and monocytes may be a novel pharmacotherapeutic target in a condition where current therapies such as bowel aperients (e.g. lactulose) are inadequate. A therapeutic strategy utilising Rifaximin, a non-absorbable antibiotic, to modulate gut bacterial which produce ammonia, a chemical known to be important in the cause of hepatic encephalopathy, could potentially lower gut-derived systemic inflammation, endotoxaemia, infection and organ dysfunction in this population improving outcomes and prolonging transplant-free survival.
We therefore plan to test if Rifaximin positively affects markers of immune dysfunction in patients with liver cirrhosis experiencing chronic hepatic encephalopathy after 30 days of treatment, as our primary research question.
Positive results from this study would support further trials into the potential benefit of using Rifaximin to improve immune function, as well as reduce the recurrence of hepatic encephalopathy, in patients with liver cirrhosis.
详细描述
Overview
The study will be designed and conducted as a double blind placebo controlled randomised controlled trial - Clinical Trial of an Investigational Medicinal Product.
This study will be performed on patients referred to King's Liver Unit for further assessment and management of chronic overt hepatic encephalopathy (≥ Grade 1) or with ≥2 episodes of overt hepatic encephalopathy in the previous 6 months.
The study will be performed on 50 patients with cirrhosis and chronic hepatic encephalopathy [25 Rifaximin and 25 placebo] aged between 18 and 75 years managed within the Liver Unit at King's College Hospital which is the largest tertiary Liver Transplant Centre within the UK. For the purposes of this study a patient will be considered to have cirrhosis if they fulfil 2 out of 3 diagnostic criteria of confirmatory liver histology, biochemistry and/or radiologic findings consistent with cirrhosis/portal hypertension, and are presenting with chronic persistent overt hepatic encephalopathy (≥ grade 1) or with ≥2 episodes of overt hepatic encephalopathy in the previous 6 months.
Patient demographics, clinical details (including Westhaven hepatic encephalopathy grade) and blood haematology, biochemistry (including venous ammonia), microbiology data and neutrophil function will be assessed and collated at baseline and following 30 and 90 days of Rifaximin therapy or placebo. Intestinal permeability will be assessed using the intestinal disaccharide test. Faecal microbiota analysis will be performed by deep pyrosequencing techniques and plasma endotoxemia will be measured (lipopolysaccharide levels) with bacterial DNA quantification as a marker of bacterial translocation. These will all be measured at 3 time points: baseline and at 30 and 90 days after initiation of Rifaximin therapy or matching placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with established cirrhosis complicated by hepatic encephalopathy
- •For the purposes of this study a patient will be considered to have cirrhosis if they fulfil two out of the three diagnostic criteria of confirmatory liver histology, biochemistry and/or radiologic findings consistent with cirrhosis/portal hypertension, and
- •are presenting with chronic persistent overt hepatic encephalopathy (≥ grade 1) or with ≥2 episodes of overt hepatic encephalopathy in the previous 6 months.
排除标准
- •Age ≤18 or ≥
- •Evidence of disseminated malignancy.
- •Known coeliac or inflammatory bowel disease.
- •Evidence of intestinal failure, intestinal obstruction and / or previous bowel resection.
- •Pre-existing immunosuppressive states including HIV infection and chronic granulomatous diseases.
- •Anti-inflammatory drug use e.g non-steroidals and immunomodulatory drug use e.g. prednisolone and azathioprine.
- •Known hypersensitivity to rifaximin or rifamycin-derivatives
- •Already receiving concomitant oral or parenteral antibiotic therapy e.g norfloxacin.
- •Infection with clostridium difficile or stool testing positive for clostridium difficile toxin in the previous 3 months.
- •Pregnancy or breast feeding women
研究组 & 干预措施
Rifaximin-α
Rifaximin-α (TARGAXAN TM, manufactured by Alfa-Wasserman, Bologna, Italy) tablets - 550mg twice daily for 90 days
干预措施: Rifaximin-α (Drug)
Placebo
Placebo tablets - 550mg twice daily for 90 days
干预措施: Placebo Oral Tablet (Drug)
结局指标
主要结局
Rifaximin-α reducing neutrophil spontaneous oxidative burst ex vivo
时间窗: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days
To test whether there is a reduction in spontaneous neutrophil oxidative burst of 50% compared to baseline (as measured by the Burstest which measures the spontaneous production of reactive oxygen species) 30 days following the start of rifaximin-α/placebo therapy.
次要结局
- Reduction in systemic inflammation(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)
- Improvement in neutrophil phenotype and function(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)
- Neutrophil bacteriocidal capacity(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)
- Alterations in faecal microbiota at 90 days(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)
- Reduction in intestinal permeability and changes in faecal biomarkers (calprotectin) at 90 days.(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)
- Changes in urinary and plasma metabonomic profile(Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days)