Two Strategies of Primary Prophylaxis of Spontaneous Bacterial Peritonitis in Severe Cirrhotic Patients With Ascites (ProPILARifax)

A Multicenter, Double-blind, Placebo-controlled Randomized Clinical Trial Comparing Two Strategies of Primary Prophylaxis of Spontaneous Bacterial Peritonitis in Severe Cirrhotic Patients With Ascites : Using or Not Using Rifaximin

We wish to perform a multicenter, double-blind RCT with two parallel-group stratified on the center, comparing rifaximin to no rifaximin (placebo) for the primary prophylaxis of SBP in 'severe' cirrhotic patients with large ascites. The primary outcome will be the 12-month survival.

Study Overview

• Status: Completed
• Conditions: Cirrhosis; Ascites; Peritonitis
• Intervention / Treatment: Drug: Rifaximin; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens
  • Angers, France
    • CHU d'Angers
  • Besançon, France
    • CHU de Besançon
  • Bondy, France
    • Hôpital Jean Verdier
  • Caen, France, 14033
    • CHU Caen
  • Clichy, France
    • Hôpital Beaujon
  • Créteil, France
    • CHIC de Créteil
  • La Tronche, France, 38700
    • CHU Grenoble
  • Lille, France
    • CHRU de Lille
  • Lyon, France, 69004
    • Hopital de la Croix-Rousse
  • Montpellier, France, 34295
    • Chu Montpellier
  • Nice, France
    • CHU de Nice
  • Paris, France
    • Hopital Pitie Salpetriere
  • Reims, France
    • CHU de reims
  • Rennes, France
    • CHU de Rennes
  • Rouen, France, 76031
    • CHU Rouen
  • Toulouse, France
    • CHU de TOULOUSE
  • Tours, France, 37044
    • CHU Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Cirrhosis diagnosed on clinical, radiological and/or histological findings
• Patients with large ascites (i.e., grade 3 ascites requiring paracentesis). Patients with grade 2 ascites are also authorized.

• Ascites with a low protein level in ascitic fluid (< 15 g/L) with one of the following three conditions:

  1. impaired renal function defined by serum creatinine ≥ 106 mmol/L, uremia ≥ 9 mmol/L or serum sodium ≤ 130 mmol/L), or
  2. severe liver impairment defined by Child-Pugh score ≥ 9 with serum total bilirubin levels ≥ 51 mmol/L.
  3. severe liver impairment defined by Child-Pugh C
• Patient who signed an informed consent form
• Patient with a social security system
• Woman must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the study if childbearing potential.
• Patients who needs a TIPS if the procedure is performed 3 months or more following the randomization
• Patients with severe alcoholic hepatitis can be considered for inclusion if the MELD score < 30 and the Maddrey Discriminant Function < 60 providing that the patient is not infected (and consequently, will not receive antibiotics) and has not yet received corticosteroid (if necessary). Patients not responding to corticosteroid at day 7 (according to the Lille score) could be include after a wash-out of steroids for a period of 7 days.

Exclusion Criteria:

• Pregnant woman or breastfeeding
• Vulnerable person regarding french law
• Individual under legal protection measure
• Individual unable to exprim his/her consent
• Person under 18 years of age and over 80 years of age
• Transplanted patients, HIV infection (or patients who deny HIV serology) or immunosuppressive therapy (including patients under corticosteroids for severe alcoholic hepatitis if the patients respond to steroids with improvement of liver function)
• Patients with a liver transplant project and an estimated waiting time for liver transplantation of 3 months or less
• Past SBP or any present bacterial infection
• Patient who have received a TIPS procedure before rhe randomization
• Patients with an alfapump
• Patient receiving antibiotics (including rifaximin) in the 7 days preceding the inclusion in this study exept for patients participating to the microbiota study (15 days).
• Hypersensitivity to rifaximin, derivatives of rifamycin or one of the constituents of the preparation
• Hepatocellular carcinoma outside the Milan criteria, other cancer at a palliative stage
• Any clinical situation with a very low short-terme prognosis (other than cirrhosis), i.e. a survival estimated lower than one month
• Gastrointestinal bleeding within 7 days
• Intestinal obstruction
• Grade 3 hepatic encephalopathy (HE) during the previous 6 months before randomization
• Chronic heart failure (stage III or IV of the New York Heart Association [NYHA] Functional Classification
• Patient judged as noncompliant
• Patients who cannot receive a clear information and who have no trusted relatives
• Patient who refuses the participation agreement by signing the information form and consent as defined in the protocol.
• Exclusion period from another biomedical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active rifaximin	Drug: Rifaximin; twice daily administration of 1 tablet containing 550 mg of active rifaximin
Placebo Comparator: Rifaximin placebo	Other: Placebo; twice daily administration of 1 rifaximin placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
death	record of death whatever the cause	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hospital mortality rate and mortality rate at 3 months	survival during hospitalization and at 3 months	3 months
Hospital mortality rate and mortality rate at 6 months	survival during hospitalization and at 6 months	6 months
Patient hospitalizations during follow-up	number of days of hospitalization during 12 months of follow-up	12 months
Quantitative variations of IL-6 in serum between day 1 and day 30	Dosage of IL-6 in serum at D1 and D30	1 month
Quantitative variations of lipopolysaccharides (LPS) in serum between day 1 and day 30	Dosage of LPS in serum at D1 and D30	1 month
Quantitative variations of copeptin in serum between day 1 and day 30	Dosage of copeptin in serum at D1 and D30	1 month
Quantitative variations of CRP in serum between day 1 and day 30	Dosage of CRP in serum at D1 and D30	1 month
Quantitative variations of von Willebrand Factor antigen in serum between day 1 and day 30	Dosage of von Willebrand Factor antigen in serum at D1 and D30	1 month
Composition of the intestinal microbiota	analyzis of microbiota (quantity and quality of main bacterial strains) in 25 patients from arms A and B at day 1, and at months 3, 6, 12 and 18	up to 18 months
Safety analysis of the study drug	Record of adverse events and serious adverse events in each arm	12 months
Incidence of spontaneous bacterial peritonitis (SBP) during follow-up	Bacterial analysis of ascites	12 months
Incidence of the other complications of liver cirrhosis during follow-up	complications of liver cirrhosis : SBP, HE, gastrointestinal bleeding and hepatorenal syndrome	12 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Besancon
• Collaborators: Alfasigma S.p.A.; LC2 PHARMA
• Investigators: Principal Investigator: Rodolphe ANTY, MD, Centre Hospitalier Universitaire de Nice; Principal Investigator: Eric Nguyen-Khac, MD, PhD, CHU Amiens; Principal Investigator: Edouard Bardou-Jacquet, MD, Rennes University Hospital; Principal Investigator: Christophe Bureau, MD, PhD, University Hospital, Toulouse; Principal Investigator: Vincent Di Martino, MD, PhD, CHRU De Besancon; Principal Investigator: Claire Francoz, MD, Hopital Beaujon, Clichy; Principal Investigator: Alexandra Heurgue-Berlot, MD, CHU de reims; Principal Investigator: Marianne Latournerie, MD, Centre Hospitalier Universitaire Dijon; Principal Investigator: Alexandre Louvet, MD, PhD, CHRU de Lille; Principal Investigator: Pierre Nahon, MD, PhD, HOPITAL JEAN VERDIER, BONDY; Principal Investigator: Frédéric Oberti, MD, University Hospital, Angers; Principal Investigator: Isabelle Rosa-Hezode, MD, CHIC de Créteil; Principal Investigator: Marika Rudler, MD, Hôpital Pitié-Salpêtrière, APHP; Principal Investigator: Matthieu Schnee, MD, Hôpital La Roche-sur-Yon; Principal Investigator: Ghassan Riachi, MD, CHU Rouen; Principal Investigator: Isabelle Ollivier, MD, CHU Caen; Principal Investigator: Laure Elkrief, MD, CHU Tours; Principal Investigator: Lucy Meunier, MD, University Hospital, Montpellier; Principal Investigator: Fanny Lebosse, MD, Hopital de la Croix-Rousse; Principal Investigator: Marie Noelle Hilleret, MD, University Hospital, Grenoble

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2018
• Primary Completion (Actual): June 3, 2022
• Study Completion (Actual): March 20, 2023

Study Registration Dates

• First Submitted: February 27, 2017
• First Submitted That Met QC Criteria: February 27, 2017
• First Posted (Actual): March 3, 2017

Study Record Updates

• Last Update Posted (Actual): April 10, 2025
• Last Update Submitted That Met QC Criteria: April 8, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: rifaximin; primary prophylaxis
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Digestive System Diseases; Peritoneal Diseases; Intraabdominal Infections; Ascites; Peritonitis; Anti-Bacterial Agents; Anti-Infective Agents; Gastrointestinal Agents; Rifaximin
• Other Study ID Numbers: ProPILA-Rifax

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No