Probiotics in the Prevention of Hepatocellular Carcinoma in Cirrhosis

NCT03853928 | Unknown DMC

• 1 other identifier: 17-036
• Study Type: interventional
• Target: 280
• Locations: 0 countries
• Sites: N/A

Brief Summary

Background. The main risk factor for the development of hepatocellular carcinoma (HCC) is cirrhosis of any etiology, with an annual risk between 1 and 6%, being currently the leading cause of death in patients with cirrhosis and the third cause of death for cancer in the world. In our country there is little information about the incidence of HCC in this population. It has been shown that there is a change in the gut microbiome (set of genetic material of microorganisms that make up the intestinal bacterial flora) as the severity of the cirrhosis progresses. This change in the microbiome has been associated with clinical decompensation events of cirrhosis. However, there are no previous studies in the world that demonstrate an impact of the change of the microbiome in cirrhosis as a precursor to the development of HCC. Our team has compared the profile of the microbiome in patients with cirrhosis with and without HCC. We observed that patients with HCC present changes in the phylum Firmicutes, genus Fusobacterium and change in the bacteroides / prevotella ratio. This pattern was associated with a pro-inflammatory profile. In murine models, it has been postulated that modulation of the gut microbiome through the use of probiotics could have a clinical role in the prevention of HCC development. This research project aims to answer the following question: in patients with cirrhosis, does the nutritional supplement with probiotics prevent HCC development? Objective: To compare the incidence of HCC through intervention with probiotics in cirrhosis. Methods: A randomized, double-blind, placebo controlled trial of probiotics in patients with Child Pugh A-B cirrhosis at 3-year follow-up. Likewise, the type of microbiome found as a predictor of the risk of HCC development will be evaluated. It will include 280 patients, 140 in each branch. Basal blood and stool samples will be obtained and every 6 months. The typing and quantification of the microbiome in samples of fecal matter will be carried out by amplifying a specific region (V3-V4) of the bacterial 16s rRNA gene. Likewise, the presence of endotoxins (LPS) and cytokines (IL6, TNF alpha) in plasma will be determined to analyze the immune environment and the expression of the TLR4 receptor in mononuclear cells.

Conditions

Microbiota; Hepatocellular Carcinoma; Cirrhosis

Keywords

Hepatocellular carcinoma; prevention; microbiome

Outcome Measures

Primary Outcomes (1)

• Number of patients developing Hepatocellular carcinoma

  The aim of this study is to evaluate the efficacy of probiotics in patients with Child Pugh A-B cirrhosis in reducing the incidence of hepatocellular carcinoma. The main measure of effectiveness in this study is the development of Hepatocarcinoma.

  3 years of follow-up

Secondary Outcomes (4)

• Description of type of gut microbiome found in cirrhosis with or without treatment with probiotics.

  Three year period

• Analyze the immunological context found in cirrhosis with or without treatment with probiotics.

  Three year period

• Number of Liver decompensation events in cirrhosis with or without treatment with probiotics.

  Three year period

• Adverse events found in cirrhosis with or without treatment with probiotics.

  Three year period

Study Arms (2)

Probiotics

EXPERIMENTAL

50 ml bottle contains Lactobacillus casei 3.3 x 107 CFU / day, Lactobacillus plantarum 3.3 x 107 CFU / day, Streptococcus faecalis 3.3 x 107 CFU / day and Bifidobacterium brevis 1.0 x 106 CFU / day (BIOFLORA®, BIOSIDUS SA, Argentina) .

Dietary Supplement: Probiotics

Placebo

PLACEBO COMPARATOR

5 ml orally every 12 hours for 10 consecutive days (Cycle, monthly). Duration of treatment Continuous, 1 cycle per month. Continuous treatment will be carried out from randomization to the development of the primary event or until the end of the study.

Dietary Supplement: Probiotics

Interventions

Probiotics DIETARY_SUPPLEMENT

Each 50 ml bottle contains Lactobacillus casei 3.3 x 107 CFU / day, Lactobacillus plantarum 3.3 x 107 CFU / day, Streptococcus faecalis 3.3 x 107 CFU / day and Bifidobacterium brevis 1.0 x 106 CFU / day (BIOFLORA®, BIOSIDUS SA, Argentina) . Medication Reference intervention. Name of the active substance: Placebo. Administration way: Oral 5 ml orally every 12 hours for 10 consecutive days (Cycle, monthly) Likewise, both branches will explicitly request the non-consumption of alcohol and the consumption of a non-hypercaloric Mediterranean diet throughout the study for all patients in each branch (ANNEXIII).

Also known as: Mediterranean diet

Placebo; Probiotics

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• signed Informed Consent (CI), obtained before carrying out any specific procedure of the study
• Clinical or histological diagnosis of cirrhosis
• Child Pugh A or B
• Presence of clinical signs of portal hypertension: esophagogastric varices or hypertensive gastropathy or edematous ascitic syndrome or encephalopathy.

You may not qualify if:

• History of hepatocellular carcinoma prior to randomization
• Solid organ transplant.
• Immunosuppressive treatment.
• Current antibiotic treatment for any reason.
• Active alcoholism: alcohol consumption in the last 3 months prior to randomization.
• History or current history of other neoplasms.
• Major surgical intervention or serious traumatic injury in the 28 days prior to randomization.
• Unstable angina (angina symptoms at rest, recently started angina, or within the last 3 months of randomization) or myocardial infarction in the 6 months prior to randomization.
• Uncontrolled cardiac arrhythmia, valvular heart disease.
• Infection grade\> 2 in progress, according to the NCA CTCAE criteria, version 4.0.
• Inflammatory bowel disease including ulcerative colitis and Crohn's disease.
• Celiac Disease.
• Diarrhea secondary to any germ or commensal, including Clostridium difficile diarrhea within 6 months prior to randomization.
• Any malabsorption disorder.
• Chronic renal failure with hemodialysis requirement.

Sponsors & Collaborators

• Austral University, Argentina: lead

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Fibrosis

Interventions

Probiotics; Diet, Mediterranean

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dietary Supplements; Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Diet, Plant-Based; Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena

Study Officials

• Federico Piñero, MD, MSCE

  Austral University, Argentina

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Julia Cremona

CONTACT

+5402304482884; MCREMONA@austral.edu.ar

Marcelo Silva, MD

CONTACT

+5402304482884; msilva@cas.austral.edu.ar

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: A randomized, double-blind, randomized controlled trial of probiotics versus placebo in patients with Child Pugh A-B cirrhosis at 3-year follow-up.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Coordinator of Clinical Research Department

Model Details: Multicenter, randomized, double-blind, placebo-controlled study of nutritional supplementation with probiotics to prevent the development of hepatocellular carcinoma in cirrhosis.

Study Record Dates

• First Submitted: February 11, 2019
• First Posted: February 26, 2019
• Study Start: May 1, 2019
• Primary Completion: May 1, 2022
• Study Completion: May 1, 2023
• Last Updated: February 27, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share