Norfloxacin Therapy for Patients With Cirrhosis and Severe Liver Failure
Information source: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Cirrhosis
Intervention: Norfloxacin (Drug); Placebo (Drug)
Phase: Phase 3
Status: Terminated
Sponsored by: Assistance Publique - Hôpitaux de Paris Official(s) and/or principal investigator(s): MOREAU RICHARD, Principal Investigator, Affiliation: APHP
Summary
Patients with advanced cirrhosis have abnormal translocation of Gram-negative bacteria
across the intestinal barrier and subsequent systemic inflammatory response. We hypothesized
that this translocation may worsen the underlying liver disease. Thus, the aim of this trial
was to assess the effects of the oral administration of norfloxacin (an antibiotic that
suppresses intestinal Gram-negative bacteria) on the development of complications of
cirrhosis.
Clinical Details
Official title: Randomized, Double-Blind, Placebo-Controlled Trial Assessing Norfloxacin in the Prevention of Complications in Patients With Cirrhosis and Severe Liver Failure
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Primary outcome: Survival rate
Secondary outcome: Survival rateNumber of patient with liver transplantation Complications : bacterial infection, renal insufficiency, hepatic encephalopathy, gastrointestinal bleeding
Detailed description:
Intestinal translocation of Gram-negative bacteria occurs in patients with advanced
cirrhosis. Long-term oral administration of 400 mg/day of norfloxacin (a fluoroquinolone
antibiotic) is known to induce selective intestinal decontamination against Gram-negative
bacteria. A randomized, double-blind, placebo-controlled trial of oral norfloxacin (400
mg/day for 1 year) has been conducted in a small series of patients with advanced cirrhosis
and low ascitic fluid protein concentrations <1. 5 g/dL. This trial showed that norfloxacin
therapy significantly increased the 1-year probability of being free of a first episode of
spontaneous bacterial peritonitis (SBP) and improved 3-month survival. In this previous
study, oral norfloxacin therapy was also found to decrease the risk of development of
hepatorenal syndrome, a very severe complication of cirrhosis. It has been suggested that
bacterial translocation, through the release of bacterial byproducts, results in systemic
inflammation and subsequent systemic vasodilation which precipitates hepatorenal syndrome.
Since systemic vasodilation plays a role in the development of ascites, bacterial byproducts
via circulatory alterations may contribute to mechanisms leading to ascites formation. It is
important to note that a randomized, double-blind, placebo-controlled trial of oral
administration of the quinolone ciprofloxacin (500 mg/day for 1 year) has been conducted in
a small series of patients with moderately severe cirrhosis, low ascitic fluid protein
concentrations (<1. 5 g/dL) and no prior history of SBP. However, ciprofloxacin therapy did
not significantly increase the 1-year probability of being free of SBP. Taken together the
findings of these 2 previous small-size trials suggest that long-term oral quinolone therapy
is effective mainly in patients with severe cirrhosis. This is why we decided to perform a
large multicenter, randomized, parallel, placebo-controlled trial assessing the effects of
norfloxacin on survival in patients with cirrhosis and severe liver failure (Child-Pugh
grade C). In addition, the effects of norfloxacin on the development of main complications
of cirrhosis will be investigated.
The primary outcome measure will be 6-month survival. The secondary outcome measures will be
the proportion of transplanted patients, the occurrence of complications (bacterial
infection, renal failure, hepatic encephalopathy and gastrointestinal bleeding). All adult
patients with severe cirrhosis might be randomized after written consent. Pregnant persons;
patient who has been treated with a quinolone in the month before the inclusion, allergy to
quinolones, hepatocellular carcinoma, or HIV infection will not be included. Patients
receive either norfloxacin or placebo once a day for 6 months. Three hundred and ninety-two
patients are necessary to decrease 6-month mortality rate from 40% in the placebo group to
25% in the norfloxacin group with a beta risk of 90% and an alpha risk of 5%. Patients will
be followed-up every month during 6 months and at 9 and 12 months.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Age > 18 years,
- Liver failure as defined by a Child-Pugh score ≥ 10 points,
- Accept to participate,
- Have health insurance.
Exclusion Criteria:
- Pregnancy,
- Patient who has been treated with a quinolone in the month before his inclusion
- Allergy to quinolones,
- Hepatocellular carcinoma, and
- HIV infection.
Locations and Contacts
Assisatnce publique Hoptitaux de Paris, Clichy 92110, France
Additional Information
Starting date: April 2010
Last updated: April 29, 2015
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