E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cirrhosis and chronic hepatic encephalopathy |
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E.1.1.1 | Medical condition in easily understood language |
Disease of the brain, associated with liver cirrhosis |
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E.1.1.2 | Therapeutic area | Body processes [G] - Physiological processes [G07] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 100000004871 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019660 |
E.1.2 | Term | Hepatic encephalopathy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To test if rifaximin reduces neutrophil spontaneous oxidative burst ex vivo in patients with cirrhosis and chronic hepatic encephalopathy after 30 days.
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E.2.2 | Secondary objectives of the trial |
To test if rifaximin reduces the development of systemic inflammation, infection, organ failure and improves patient survival over 90 days. This will include analyses for changes in intestinal permeability, alterations in faecal microbiota and faecal biomarkers (e.g. calprotectin), systemic endotoxemia and immune dysfunction
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with established cirrhosis complicated by hepatic encephalopathy will be recruited to this study. 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 HE in the previous 6 months. |
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E.4 | Principal exclusion criteria |
• Age <18 or >75 years
• Evidence of disseminated malignancy.
- isolated hepatocellular carcinoma without evidence of secondary spread is not an exclusion criteria.
• 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
• Exposure to standard Rifaximin therapy in the 12 weeks prior to recruitment.
• Already receiving concomitant oral or parenteral antibiotic therapy e.g norfloxacin, at the time of recruitment
• Infection with clostridium difficile or stool testing positive for clostridium difficile toxin in the previous 3 months.
• Pregnancy or breast feeding women.
• Patients with portacaval shunts such as transjugular intrahepatic portosystemic shunts will not be excluded.
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E.5 End points |
E.5.1 | Primary end point(s) |
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). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
30 days following the start of rifaximin-α/placebo therapy. |
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E.5.2 | Secondary end point(s) |
i. A reduction in systemic inflammation as measured by plasma endotoxemia, bacterial DNA quantification and plasma pro-inflammatory cytokine profile at 90 days.
ii. An improvement in neutrophil bacteriocidal capacity as measured by the Phagotest which utilises opsonised E. coli at 30 and 90 days.
iii. An improvement in neutrophil phenotype and function including baseline and LPS-induced toll-like receptor 4 expression and intracellular cytokine production at 30 and 90 days.
iv. Alterations in faecal microbiota at 90 days.
v. Reduction in intestinal permeability and changes in faecal biomarkers (calprotectin) at 90 days.
vi. Changes in urinary and plasma metabonomic profile as measured by proton MR spectroscopy at 90 days.
vii. Development of recurrent overt hepatic encephalopathy, organ failure and infection during the 90 day follow up.
viii. Improvement in Trails A and B neuropsychiatric test score at 30 and 90 days.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 14 |