Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis

Study Overview
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Brief Summary
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Background Prophylaxis of SBP is indicated in three high-risk populations: patients with acute gastrointestinal hemorrhage, patients with low total protein content in ascitic fluid, and patients with a previous history of SBP (secondary prophylaxis). Selective intestinal decontamination with norfloxacin, a quinolone with relatively poor gastrointestinal absorption and with antibacterial activity against GNB, is the most commonly used regimen, but several concerns have been recently raised in this regard. A recent network meta-analysis published by the investigators showed that rifaximin determines interesting results in this setting but needs to be tested in further trials. Given its favorable safety profile and the relatively low cost, rifaximin could represent the antibiotic of choice in long-term prophylaxis. Study Objective To establish the prophylactic efficacy, of rifaximin as compared to norfloxacin in cirrhotic patients with low protein content in the ascitic fluid. Protocol design Phase III, two-arms, open-label, multi-center, randomized controlled trial. Trial population Patients with cirrhosis and ascites and with low protein content in the ascitic fluid (≤1.5 g/dL) and with deteriorated liver function (Child-Pugh score ≥B9, serum bilirubin level ≥3 mg/dL) or impaired renal function (creatinine ≥1.2 mg/dL blood urea nitrogen level ≥25 mg/dL or hyponatremia ≤130 milliequivalent [mEq]/L) Protocol Treatments The Treatment arm will undergo rifaximin 1200 mg/day in 3 doses. The Control arm will undergo norfloxacin 400 mg 1/die for 6 months Primary Endpoint Prevention of spontaneous bacterial peritonitis episodes. Secondary Endpoints Prevention of mortality (both all-cause and liver-related mortality) Preventions of hepatorenal syndrome Prevention of other infections Adverse events Sample size and study duration It will be planned to enroll 322 patients (161 per arms) within 18 months. A minimum follow up of 6 months from the last patient recruited will be required.

Detailed Description
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Background Spontaneous bacterial peritonitis (SBP) is a commonly observed and severe complication in patients with cirrhosis and ascites, with a reported prevalence ranging from 10% to 25% in hospitalized cirrhotic patients1. Given the high mortality rate and the risk of developing hepato-renal syndrome (HRS), prophylaxis of SBP is indicated particularly in three high-risk populations: patients with acute gastrointestinal hemorrhage, patients with low total protein content in ascitic fluid, and patients with a previous history of SBP (secondary prophylaxis)2. The ideal prophylactic agent should be safe, affordable, and effective particularly against anaerobic bacteria translocating from the gut as most episodes of SBP are thought to result from the translocation of enteric Gram-negative bacilli (GNB)3. Selective intestinal decontamination with norfloxacin, a quinolone with relatively poor gastrointestinal absorption and with antibacterial activity against GNB, is the most commonly used regimen4, but several concerns have been recently raised in this regard. In fact, the epidemiology of bacterial infections in cirrhosis is evolving with an increasing incidence of infections caused by quinolone-resistant bacteria5; moreover, primary prophylaxis in low-protein ascitic patients requires long-term antibiotic regimens (whose exact duration is still matter of debate), hence less expensive and better tolerated agents such as rifaximin have been tested with conflicting results6. A recent network meta-analysis published by the investigators showed that rifaximin determines interesting results in this setting but needs to be tested in further trials7. Given its favorable safety profile and the relatively low cost, rifaximin could represent the antibiotic of choice in long-term prophylaxis. Study Objective To establish the prophylactic efficacy, of rifaximin as compared to norfloxacin in cirrhotic patients with low protein content in the ascitic fluid. Protocol design Phase III, two-arms, open-label, multi-center, randomized controlled trial. Trial population Patients with cirrhosis and ascites and with low protein content in the ascitic fluid (≤1.5 g/dL) and with deteriorated liver function (Child-Pugh score ≥B9, serum bilirubin level ≥3 mg/dL) or impaired renal function (creatinine ≥1.2 mg/dL blood urea nitrogen level ≥25 mg/dL or hyponatremia ≤130 mEq/L) Protocol Treatments The Treatment arm will undergo rifaximin 1200 mg/day in 3 doses. The Control arm will undergo norfloxacin 400 mg 1/die for 6 months Protocol Baseline evaluation will include history and physical examination, liver and renal tests, ascitic fluid analysis and culture, fresh urine sediment, and abdominal ultrasonography. Treatment will start immediately after randomization. Follow-up visits will be performed every 4 weeks. Treatment compliance will be assessed by interviewing the patient and by tablet count at each visit. A patient will be considered noncompliant when the study medication will not be taken for 7 days or more, or will fail to take more than 20 % of their pills or miss two or more visits. Medications will be interrupted when patients develop an episode of SBP (ascitic fluid neutrophil count[ 250 cell/ml with or without clinical evidence), or have upper gastrointestinal (GIT) bleeding or receive a liver transplant. Diagnostic paracentesis will be performed when clinically indicated. Diagnosis of spontaneous bacteremia, SBP, urinary infection, and other infections will be made by biological fluid cultures and analysis; type-1 and type-2 HRS will be diagnosed according to the criteria of the International Ascites Club. Spontaneous bacteremia and SBP will be treated with ceftriaxone. Primary Endpoint Prevention of spontaneous bacterial peritonitis episodes. Secondary Endpoints Prevention of mortality (both all-cause and liver-related mortality) Preventions of hepatorenal syndrome Prevention of other infections Adverse events Sample size and study duration It will be planned to enroll 322 patients (161 per arms) within 18 months. A minimum follow up of 6 months from the last patient recruited will be required. Treatment strategy Patients complying with the eligibility criteria will be randomized in a 1:1 fashion to receive rifaximin 1200 mg/day or norfloxacin 400 mg/day. No cross-over will be allowed.

Official Title
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Rifaximin Versus Norfloxacin in the Primary Prophylaxis of Spontaneous Bacterial Peritonitis

Conditions
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Spontaneous Bacterial Peritonitis

Intervention / Treatment
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* Drug: Rifaximin
* Drug: Norfloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with cirrhosis and ascites and with low protein content in the ascitic fluid (≤1.5 g/dL) and with deteriorated liver function (Child-Pugh score ≥B9, serum bilirubin level ≥3 mg/dL) or impaired renal function (creatinine ≥1.2 mg/dL blood urea nitrogen level ≥25 mg/dL or hyponatremia ≤130 mEq/L) Exclusion Criteria: Age under 18 years Previous history of SBP Previous use of antibiotics within the previous two weeks Previous GIT bleeding within one month Resolving ascites for one month after diuretic therapy Liver malignancy, organic renal disease Human immunodeficiency virus infection Known hypersensitivity to planned drugs Refusal to provide informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br>Rifaximin 1200 mg/day in 3 doses | Drug: Rifaximin<br>* Rifaximin pills 400 mg x 3/day<br>|
| Active Comparator: Control Group<br>Norfloxacin 400 mg/day in one dose | Drug: Norfloxacin<br>* Norlfloxacin 400 mg 1 pill/day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of Spontaneous Bacterial Peritonitis | Rate of episodes of spontaneous bacterial peritonitis | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevention of mortality | Rate of deaths observed | 6 months | 
| Prevention of hepatorenal syndrome | Rate of hepatorenal syndrome episodes | 6 months | 
| Prevention of other infections | Rate of other infections | 6 months | 
| Adverse Events | Rate of adverse events | 6 months |