Norfloxacin Therapy for Patients With Cirrhosis and Severe Liver Failure (NORFLOCIR)

Randomized, Double-Blind, Placebo-Controlled Trial Assessing Norfloxacin in the Prevention of Complications in Patients With Cirrhosis and Severe Liver Failure

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.

Study Overview

• Status: Terminated
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: Norfloxacin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 291
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clichy, France, 92110
    • Assisatnce publique Hoptitaux de Paris

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Norfloxacin; Patients with severe cirrhosis treated with norfloxacin	Drug: Norfloxacin; 400 mg/day (per os) for 6 months
PLACEBO_COMPARATOR: Placebo; Patients with severe cirrhosis treated with placebo	Drug: Placebo; 1 pill/day (per os) for 6 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Survival rate	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Survival rate	12-month follow-up
Number of patient with liver transplantation	12 months
Complications : bacterial infection, renal insufficiency, hepatic encephalopathy, gastrointestinal bleeding	12 months

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: MOREAU RICHARD, APHP

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): November 1, 2014
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: December 21, 2009
• First Submitted That Met QC Criteria: December 22, 2009
• First Posted (ESTIMATE): December 23, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): December 9, 2015
• Last Update Submitted That Met QC Criteria: December 8, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: severe cirrhosis; Patients with severe cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Liver Diseases; Fibrosis; Liver Failure; Liver Cirrhosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Norfloxacin
• Other Study ID Numbers: P071220