A trial to determine if rifaximin is more efficient than placebo in treating systemic inflammation and neutrophil (white blood cells) malfunction in patients with cirrhosis and chronic hepatic encephalopathy

• Register: EUCTR
• Last refreshed on: 3 April 2017
• Main ID: EUCTR2013-004708-20-GB
• Date of registration: 03/03/2014
• Prospective Registration: Yes
• Primary sponsor: King's College London
• Public title: A trial to determine if rifaximin is more efficient than placebo in treating systemic inflammation and neutrophil (white blood cells) malfunction in patients with cirrhosis and chronic hepatic encephalopathy
• Scientific title: 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
• Date of first enrolment: 27/03/2014
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2013-004708-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

United Kingdom

Contacts

• Name: Debbie Shawcross
• Affiliation: King's College London

• Name: Debbie Shawcross
• Affiliation: King's College London

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 50

Exclusion criteria:
• Age ??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.



Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Body processes [G] - Physiological processes [G07]

Cirrhosis and chronic hepatic encephalopathy
MedDRA version: 18.0 Level: LLT Classification code 10024667 Term: Liver cirrhosis System Organ Class: 100000004871
MedDRA version: 18.0 Level: PT Classification code 10019660 Term: Hepatic encephalopathy System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Trade Name: Targaxan
Product Name: Targaxan
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: RIFAXIMIN
CAS Number: 80621-81-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 550-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Nasogastric use (Noncurrent)

Primary Outcome(s)

Main Objective: To test if rifaximin reduces neutrophil spontaneous oxidative burst ex vivo in patients with cirrhosis and chronic hepatic encephalopathy after 30 days.

Secondary Objective: 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

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).

Timepoint(s) of evaluation of this end point: 30 days following the start of rifaximin-a/placebo therapy.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: As per E.5.2 above

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.

Secondary ID(s)

RIFSYS

Source(s) of Monetary Support

Norgine Pharmaceuticals UK Limited

Secondary Sponsor(s)

King's College Hospital NHS Foundation Trust