Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
Primary Purpose
Spontaneous Bacterial Peritonitis
Status
Unknown status
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Rifaximin
Norfloxacin
Sponsored by
About this trial
This is an interventional prevention trial for Spontaneous Bacterial Peritonitis
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.
Sites / Locations
- Ospedali Riuniti Foggia
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Intervention Group
Control Group
Arm Description
Rifaximin 1200 mg/day in 3 doses
Norfloxacin 400 mg/day in one dose
Outcomes
Primary Outcome Measures
Prevention of Spontaneous Bacterial Peritonitis
Rate of episodes of spontaneous bacterial peritonitis
Secondary Outcome Measures
Prevention of mortality
Rate of deaths observed
Prevention of hepatorenal syndrome
Rate of hepatorenal syndrome episodes
Prevention of other infections
Rate of other infections
Adverse Events
Rate of adverse events
Full Information
NCT ID
NCT04159870
First Posted
November 7, 2019
Last Updated
February 15, 2021
Sponsor
Ospedali Riuniti di Foggia
1. Study Identification
Unique Protocol Identification Number
NCT04159870
Brief Title
Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
Official Title
Rifaximin Versus Norfloxacin in the Primary Prophylaxis of Spontaneous Bacterial Peritonitis
Study Type
Interventional
2. Study Status
Record Verification Date
February 2021
Overall Recruitment Status
Unknown status
Study Start Date
November 5, 2019 (Actual)
Primary Completion Date
November 20, 2021 (Anticipated)
Study Completion Date
December 20, 2021 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ospedali Riuniti di Foggia
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spontaneous Bacterial Peritonitis
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
322 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Intervention Group
Arm Type
Experimental
Arm Description
Rifaximin 1200 mg/day in 3 doses
Arm Title
Control Group
Arm Type
Active Comparator
Arm Description
Norfloxacin 400 mg/day in one dose
Intervention Type
Drug
Intervention Name(s)
Rifaximin
Intervention Description
Rifaximin pills 400 mg x 3/day
Intervention Type
Drug
Intervention Name(s)
Norfloxacin
Intervention Description
Norlfloxacin 400 mg 1 pill/day
Primary Outcome Measure Information:
Title
Prevention of Spontaneous Bacterial Peritonitis
Description
Rate of episodes of spontaneous bacterial peritonitis
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Prevention of mortality
Description
Rate of deaths observed
Time Frame
6 months
Title
Prevention of hepatorenal syndrome
Description
Rate of hepatorenal syndrome episodes
Time Frame
6 months
Title
Prevention of other infections
Description
Rate of other infections
Time Frame
6 months
Title
Adverse Events
Description
Rate of adverse events
Time Frame
6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
Ospedali Riuniti Foggia
City
Foggia
ZIP/Postal Code
71122
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
11786970
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.
Results Reference
result
PubMed Identifier
20633946
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.
Results Reference
result
PubMed Identifier
29427501
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.
Results Reference
result
PubMed Identifier
1397884
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.
Results Reference
result
PubMed Identifier
10453941
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.
Results Reference
result
PubMed Identifier
30246636
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.
Results Reference
result
PubMed Identifier
30920712
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.
Results Reference
result
PubMed Identifier
28994123
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.
Results Reference
result
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Rifaximin Versus Norfloxacin in Spontaneous Bacterial Peritonitis
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