Norfloxacin Therapy for Patients With Cirrhosis and Severe Liver Failure

NCT ID: NCT01037959

Last Updated: 2015-12-09

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 291 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2015-11-30

Brief 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.

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.

Conditions

Cirrhosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Norfloxacin

Patients with severe cirrhosis treated with norfloxacin

Group Type: ACTIVE_COMPARATOR

Norfloxacin

Intervention Type: DRUG

400 mg/day (per os) for 6 months

Placebo

Patients with severe cirrhosis treated with placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1 pill/day (per os) for 6 months

Interventions

Norfloxacin

400 mg/day (per os) for 6 months

Intervention Type: DRUG

Placebo

1 pill/day (per os) for 6 months

Intervention Type: DRUG

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MOREAU RICHARD

Role: PRINCIPAL_INVESTIGATOR

APHP

Locations

Assisatnce publique Hoptitaux de Paris

Clichy, , France

Countries

France

References

Moreau R, Elkrief L, Bureau C, Perarnau JM, Thevenot T, Saliba F, Louvet A, Nahon P, Lannes A, Anty R, Hillaire S, Pasquet B, Ozenne V, Rudler M, Ollivier-Hourmand I, Robic MA, d'Alteroche L, Di Martino V, Ripault MP, Pauwels A, Grange JD, Carbonell N, Bronowicki JP, Payance A, Rautou PE, Valla D, Gault N, Lebrec D; NORFLOCIR Trial Investigators. Effects of Long-term Norfloxacin Therapy in Patients With Advanced Cirrhosis. Gastroenterology. 2018 Dec;155(6):1816-1827.e9. doi: 10.1053/j.gastro.2018.08.026. Epub 2018 Aug 23.

Reference Type: DERIVED

PMID: 30144431 (View on PubMed)

Other Identifiers

P071220

Identifier Type: -

Identifier Source: org_study_id