Clinical trial NCT04159870: Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
Official title: Rifaximin Versus Norfloxacin in the Primary Prophylaxis of Spontaneous Bacterial Peritonitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Spontaneous Bacterial Peritonitis
Lead sponsor: Ospedali Riuniti di Foggia
Sponsor class: OTHER
First posted: 2019-11-12
Enrollment: 322
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Prevention of Spontaneous Bacterial Peritonitis
timeFrame: 6 months
Secondary outcomes:
measure: Prevention of mortality
timeFrame: 6 months
measure: Prevention of hepatorenal syndrome
timeFrame: 6 months
measure: Prevention of other infections
timeFrame: 6 months
measure: Adverse Events
timeFrame: 6 months
Other outcomes:
Locations:
city: Foggia
country: Italy
facility: Ospedali Riuniti Foggia
Study officials:
References:
citation: Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, Rodes J. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology. 2002 Jan;35(1):140-8. doi: 10.1053/jhep.2002.30082.
citation: European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010 Sep;53(3):397-417. doi: 10.1016/j.jhep.2010.05.004. Epub 2010 Jun 1. No abstract available.
citation: Piano S, Brocca A, Mareso S, Angeli P. Infections complicating cirrhosis. Liver Int. 2018 Feb;38 Suppl 1:126-133. doi: 10.1111/liv.13645.
citation: Soriano G, Guarner C, Tomas A, Villanueva C, Torras X, Gonzalez D, Sainz S, Anguera A, Cusso X, Balanzo J, et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology. 1992 Oct;103(4):1267-72. doi: 10.1016/0016-5085(92)91514-5.
citation: Aparicio JR, Such J, Pascual S, Arroyo A, Plazas J, Girona E, Gutierrez A, de Vera F, Palazon JM, Carnicer F, Perez-Mateo M. Development of quinolone-resistant strains of Escherichia coli in stools of patients with cirrhosis undergoing norfloxacin prophylaxis: clinical consequences. J Hepatol. 1999 Aug;31(2):277-83. doi: 10.1016/s0168-8278(99)80225-6.
citation: Menshawy A, Mattar O, Barssoum K, AboEl-Naga AM, Salim HM, Mohamed AMF, Elgebaly A, Abd-Elsalam S. Safety and Efficacy of Rifaximin in Prophylaxis of Spontaneous Bacterial Peritonitis: A Systematic Review and Meta-analysis. Curr Drug Targets. 2019;20(4):380-387. doi: 10.2174/1389450119666180924145156.
citation: Facciorusso A, Papagiouvanni I, Cela M, Buccino VR, Sacco R. Comparative efficacy of long-term antibiotic treatments in the primary prophylaxis of spontaneous bacterial peritonitis. Liver Int. 2019 Aug;39(8):1448-1458. doi: 10.1111/liv.14109. Epub 2019 Apr 25.
citation: Goel A, Rahim U, Nguyen LH, Stave C, Nguyen MH. Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis. Aliment Pharmacol Ther. 2017 Dec;46(11-12):1029-1036. doi: 10.1111/apt.14361. Epub 2017 Oct 9.