Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
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.
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.
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.