Study of the Effect of Adjunctive Vivomixx® in Patients With Cirrhosis and Spontaneous Bacterial Peritonitis (SBP)

Study of the Effect of Adjunctive Vivomixx® in Addition to Antibiotics on Systemic and Cerebral Inflammatory Response in Patients With Cirrhosis and Spontaneous Bacterial Peritonitis (SBP)

Study Design: Double-blind placebo-controlled clinical trial

Study Duration:2 years

Study Center: Hospital de la Santa Creu i Sant Pau, Barcelona (single center)

Objectives: To assess the effect of adjunctive Vivomixx® on bacterial translocation in patients with cirrhosis and SBP

Number of Subjects: 30

Main Inclusion Criteria: Patients with cirrhosis hospitalized with an episode of SBP at Hospital de la Santa Creu i Sant Pau

Study Product, Dose, Route, Regimen: Vivomixx ® sachets containing 450 x 109 bacteria, 2 every 12 hours during hospitalization (n=15), or placebo (n=15)

Duration of administration: During hospitalization due to SBP episode

Hypothesis: The adjunctive treatment with Vivomixx® in patients with cirrhosis and SBP could decrease bacterial translocation and systemic and cerebral proinflammatory state. This would result in a faster SBP resolution, a decrease in the incidence of complications and an improvement in cognitive function.

Study Overview

• Status: Withdrawn
• Conditions: Spontaneous Bacterial Peritonitis
• Intervention / Treatment: Drug: Vivomixx®; Drug: Placebo

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Hospital de la Santa Creu i Sant Pau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with cirrhosis hospitalized with an episode of SBP at Hospital de la Santa Creu i Sant Pau.

Cirrhosis will be diagnosed by clinical, analytical and ultrasonographic findings or by liver biopsy. SBP will be diagnosed by an ascitic fluid neutrophil count > 250/mm3 with or without positive culture .

Exclusion Criteria:

• Advanced hepatocellular carcinoma (beyond Milan's criteria) or any other malignancy.
• Advanced liver insufficiency [MELD (model for end-stage liver disease) >25].
• Active alcohol intake (in the previous 3 months).
• Neurological disease.
• Marked symptomatic comorbidities (cardiac, pulmonary, renal, untreated active depression, HIV infection).
• Previous antibiotic treatment, including norfloxacin and rifaximin.
• Septic shock, ileus, need for tracheal intubation or intensive care unit.
• Immunomodulatory drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Vivomixx®; Vivomixx® is a probiotic mixture of 8 proprietary strains. Thirty consecutive patients with cirrhosis and SBP will be randomized to receive Vivomixx® , sachets containing 450 x 109 bacteria, 2 every 12 hours during all the hospitalization until a maximum of 30 days (n=15), or placebo (n=15). All patients will receive endovenous antibiotics and also intravenous albumin 1.5 g/kg weight the first day and 1 g/kg weight the third day of treatment. The management of patients will follow current guidelines.	Drug: Vivomixx®; Vivomixx® is a probiotic mixture of 8 proprietary strains, namely Streptococcus thermophilus DSM 24731, bifidobacteria (B. breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737) and lactobacilli (L. paracasei DSM 24733, L. acidophilus DSM 24735, L. delbrueckii subsp bulgaricus DSM 24734, L. plantarum DSM 24730). The active agent will be supplied as a 4.4g sachet at a dose of 450 billion live bacteria per sachet with maltose and silicon dioxide as excipients.; Other Names: Vivomixx ®
PLACEBO_COMPARATOR: Placebo; Placebo will be formulated as identical in appearance and administered according to the same schedule as the active agent. Placebo contains maltose and silicon dioxide as inactive agent.	Drug: Placebo; Placebo will be formulated as identical in appearance and administered according to the same schedule as the active agent. Placebo contains maltose and silicon dioxide as inactive agent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in bacterial translocation (composite measure)	Bacterial translocation will be evaluated by change from baseline in bacterial DNA in blood and ascitic fluid, lipopolysaccharide binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and intestinal bile acid binding protein (I-BABP) in blood, and polyethylene glycols (PEG) and claudin 3 in urine .	At baseline, daily until infection resolution (an expected average of 7 days) and at three months after discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in systemic inflammatory response and systemic oxidative damage (composite measure)	Systemic Inflammation and immune response will be evaluated by change from baseline in serum C reactive protein (CRP), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IL-10, IL-12, IL-18, IL-22, sTNFR-1, sTNFR-2, sCD163, matrix metalloproteinase (MMP) -9, interferon (IFN)-γ, vascular endothelial growth factor (VEGF), claudin-5, nitrites and nitrates in serum and ascitic fluid. Systemic oxidative damage will be evaluated by change from baseline in determination of malondialdehyde (MDA) in blood.	At baseline, daily until infection resolution (an expected average of 7 days) and at three months after discharge
Changes in cognitive function (composite measure)	Cognitive function will be evaluated by change from baseline in Trail-Making Test A (TMT-A), Trail-Making Test B (TMT-B), and Digit Symbol Test (DST).	At baseline at infection resolution (an expected average of 7 days)
Changes in brain inflammation (composite measure)	Brain inflammation will be evaluated by change from baseline in MRI and different biomarkers of neuroinflammation. A designed MR protocol will be produced, including imaging using different sequences, and more biochemical (MR spectroscopy) and functional (DTI) studies.	At baseline (during the first 12-24 hours after inclusion in the study) and after 3 days of treatment.

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (ANTICIPATED): December 1, 2017
• Study Completion (ANTICIPATED): December 1, 2018

Study Registration Dates

• First Submitted: August 26, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (ESTIMATE): September 17, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): December 15, 2016
• Last Update Submitted That Met QC Criteria: December 14, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Peritoneal Diseases; Intraabdominal Infections; Peritonitis
• Other Study ID Numbers: IIBSP-VSL-2014-49