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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01037959
First received: December 21, 2009
Last updated: August 25, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Cirrhosis
Drug: Norfloxacin
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Randomized, Double-Blind, Placebo-Controlled Trial Assessing Norfloxacin in the Prevention of Complications in Patients With Cirrhosis and Severe Liver Failure

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Survival rate [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Survival rate [ Time Frame: 12-month follow-up ] [ Designated as safety issue: Yes ]
  • Number of patient with liver transplantation [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • Complications : bacterial infection, renal insufficiency, hepatic encephalopathy, gastrointestinal bleeding [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]

Enrollment: 291
Study Start Date: April 2010
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Norfloxacin
Patients with severe cirrhosis treated with norfloxacin
Drug: Norfloxacin
400 mg/day (per os) for 6 months
Other Name: NORFLOXACIN
Placebo Comparator: Placebo
Patients with severe cirrhosis treated with placebo
Drug: Placebo
1 pill/day (per os) for 6 months
Other Name: 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01037959

Locations
France
Assisatnce publique Hoptitaux de Paris
Clichy, France, 92110
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: MOREAU RICHARD APHP
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01037959     History of Changes
Other Study ID Numbers: P071220
Study First Received: December 21, 2009
Last Updated: August 25, 2014
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
severe cirrhosis
Patients with severe cirrhosis

Additional relevant MeSH terms:
Liver Cirrhosis
Liver Failure
Liver Diseases
Digestive System Diseases
Hepatic Insufficiency
Norfloxacin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 18, 2014