Clinical trial NCT03069131: Two Strategies of Primary Prophylaxis of Spontaneous Bacterial Peritonitis in Severe Cirrhotic Patients With Ascites
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cirrhosis
Ascites
Peritonitis
Keywords: primary prophylaxis
rifaximin
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
Collaborators: name: Alfasigma S.p.A.
name: LC2 PHARMA
First posted: 2017-03-03
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: death
timeFrame: 12 months
Secondary outcomes:
measure: Hospital mortality rate and mortality rate at 3 months
timeFrame: 3 months
measure: Hospital mortality rate and mortality rate at 6 months
timeFrame: 6 months
measure: Incidence of spontaneous bacterial peritonitis (SBP) during follow-up
timeFrame: 12 months
measure: Incidence of the other complications of liver cirrhosis during follow-up
timeFrame: 12 months
measure: Patient hospitalizations during follow-up
timeFrame: 12 months
measure: Quantitative variations of IL-6 in serum between day 1 and day 30
timeFrame: 1 month
measure: Quantitative variations of lipopolysaccharides (LPS) in serum between day 1 and day 30
timeFrame: 1 month
measure: Quantitative variations of copeptin in serum between day 1 and day 30
timeFrame: 1 month
measure: Quantitative variations of CRP in serum between day 1 and day 30
timeFrame: 1 month
measure: Quantitative variations of von Willebrand Factor antigen in serum between day 1 and day 30
timeFrame: 1 month
measure: Composition of the intestinal microbiota
timeFrame: up to 18 months
measure: Safety analysis of the study drug
timeFrame: 12 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Besançon
country: France
facility: CHU de Besançon
city: Bondy
country: France
facility: Hôpital Jean Verdier
city: Caen
country: France
facility: CHU Caen
city: Clichy
country: France
facility: Hôpital Beaujon
city: Créteil
country: France
facility: CHIC de Créteil
city: La Tronche
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHRU de Lille
city: Lyon
country: France
facility: Hopital de la croix-rousse
city: Montpellier
country: France
facility: CHU Montpellier
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière
city: Reims
country: France
facility: CHU de Reims
city: Rennes
country: France
facility: CHU de Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Toulouse
country: France
facility: CHU de Toulouse
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: Centre Hospitalier Universitaire de Nice
name: Rodolphe Anty, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Rennes University Hospital
name: Edouard Bardou-Jacquet, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Toulouse
name: Christophe Bureau, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU de Besançon
name: Vincent Di Martino, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Beaujon, Clichy
name: Claire Francoz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Reims
name: Alexandra Heurgue-Berlot, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Universitaire Dijon
name: Marianne Latournerie, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHRU de Lille
name: Alexandre Louvet, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Jean Verdier, Bondy
name: Pierre Nahon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Angers
name: Frédéric Oberti, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHIC de Créteil
name: Isabelle Rosa-Hezode, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Pitié-Salpêtrière, APHP
name: Marika Rudler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital La Roche-sur-Yon
name: Matthieu Schnee, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Rouen
name: Ghassan Riachi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU CAEN
name: Isabelle Ollivier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Amiens
name: Eric Nguyen-Khac, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Tours
name: Laure Elkrief, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Montpellier
name: Lucy Meunier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hopital de la Croix-Rousse
name: Fanny Lebosse, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Grenoble
name: Marie Noelle Hilleret, MD
role: PRINCIPAL_INVESTIGATOR
References: