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Influence of Probiotics Administration Before Liver Resection in Liver Disease (LIPROCES)

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ClinicalTrials.gov Identifier: NCT02021253
Recruitment Status : Completed
First Posted : December 27, 2013
Last Update Posted : May 15, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Rouen

Tracking Information
First Submitted Date  ICMJE July 3, 2013
First Posted Date  ICMJE December 27, 2013
Last Update Posted Date May 15, 2018
Study Start Date  ICMJE April 2013
Actual Primary Completion Date April 12, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2013)
Area under the plasma concentration versus time curve (AUC) of endotoxins circulating levels [ Time Frame: -12, 3, 12,24, 72, 120 hours at time of surgery ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Influence of Probiotics Administration Before Liver Resection in Liver Disease
Official Title  ICMJE Circulating Endotoxemia After Liver Resection for Hepatocellular Carcinoma in Liver Disease - Influence of Preoperative Administration of Probiotics
Brief Summary

Surgical resection is one of the curative treatment modalities for HCC. Limits are postoperative septic and liver functional complications related to an increase in bacterial translocation and systemic endotoxemia. Bacterial translocation is a passage of bacteria and bacterial degradation products from the intestine to the portal circulation. The endotoxemia secondary to bacterial translocation, stimulates endothelial production of nitric oxide (NO). NO is also a potent inducer of membrane instability, responsible for an increase in the permeability of the vascular endothelium and intestinal mucosa, possibly contributing to a worsening of bacterial translocation.

Probiotics are live microorganisms which when administered in adequate amounts, provide a health benefit on the host ((Health and Nutritional Properties of Probiotics in Food Including Powder Milk with Live Lactic Acid Bacteria - Cordoba Argentina October 2001). Data from experimental and clinical literature show a significant effect of probiotics on the improvement of liver function and a decrease in infectious complications in patients with chronic liver disease. The proposed study would evaluate the effect preventive and therapeutic in a population of surgical patients, in whom the intestinal portal and hepatic inflammation promotes postoperative complications.

Detailed Description

The aim of this study is to evaluate the effect of the administration of probiotics on intestinal barrier function in patients with chronic liver disease (fibrosis stage F3 or F4) operated for hepatocellular carcinoma.

After hepatectomy, kinetic of endotoxemia have been studied previously and the evolution will be summarized by the area under the plasma concentration versus time curve (AUC) of circulating endotoxin levels measured before surgery and at 5 different times analysis after hepatectomy. At 12 hours, portal hypertension and its consequences on gut permeability (impaired barrier function, bacterial translocation) are highest with peak of circulating endotoxins. The decreasing of endotoxemia curve is observed between the 2nd and 3rd day (end of liver regeneration and early liver architectural reorganization). On the 5th day, persist measurable but not deleterious to liver restructured and theoretically functional rates.

Then the main criterion to demonstrate the effectiveness of a diet enriched with probiotics is the AUC of circulating levels of endotoxins ((pg/ml) using the Limulus amebocyte lysate (LAL) assay) observed for each patient. Endotoxin levels were analysed on samples of peripheral blood. The two arms of equal size will be considered significantly different when compared to the AUC of circulating levels of endotoxin if the null hypothesis (AUC is the same for both arms) is rejected in favor of the alternative hypothesis (AUC differs between the two arms - Wilcoxon test)

In order to estimate the sample size to distinguish between the two hypotheses with sufficient power, the median AUC in arm without probiotics be used to form two groups of patients in each arm. Thus, half of the patients without probiotics have a higher median AUC arms. Then, this proportion may be compared to the proportion of patients with probiotics have an AUC greater than the median of the group without probiotics.

The secondary endpoints are:

  • Evaluation of systemic inflammation by assay of inflammatory cytokines
  • IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFNa, TNFa
  • CRP
  • Leukocyte count
  • The post-operative liver function monitored in the usual manner
  • Standard Liver function tests between J1 and J5 (Bilirubin, prothrombin, ammonia)
  • Indocyanine green clearance with measuring retention rates at 15 minutes between J1 and J3
  • Monitoring of overall postoperative complications and specifically liver failure and infectious complications at 3 months.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Other
Condition  ICMJE
  • Liver Fibrosis
  • Liver Cirrhosis
  • Permeability; Increased
  • Hepatocellular Carcinoma
Intervention  ICMJE
  • Dietary Supplement: Probiotic
    Lactibiane TOLERANCE vs Placebo
    Other Name: Lactibiane TOLERANCE (PILeJe) 5 probiotics association
  • Dietary Supplement: Placebo
Study Arms  ICMJE
  • Placebo Comparator: Placebo of Probiotics

    Placebo: Composition: Each capsule contains 560 mg:

    • 459 mg of corn starch
    • 6 mg of magnesium stearate

    Dosage: 2 capsules / day, in the morning at sunrise, one at bedtime.

    Methods of administration: Oral.

    Duration of treatment: 14 days

    Intervention: Dietary Supplement: Placebo
  • Active Comparator: Probiotics- Lactibiane Tolerance

    Active substance mixture of lactic 10% Bifidobacterium lactis LA 303, 10% Lactobacillus acidophilus LA 201, LA 40% Lactobacillus plantarum 301, 20% Lactobacillus salivarius LA 302, LA 20% Bifidobacterium lactis 304 Dosage: 10 X 10^9 probiotic / capsule

    Composition: One capsule of 560 mg contains Lactibiane tolerance:

    • 345 mg of corn starch
    • 114 mg premix lactic
    • 6 mg of magnesium stearate Excipients: magnesium stearate

    Method of administration: Oral

    Dosage: 2 capsules per day for 14 days in two doses: one capsule at sunrise, one capsule at bedtime;

    Intervention: Dietary Supplement: Probiotic
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 19, 2013)
64
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 12, 2018
Actual Primary Completion Date April 12, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Agreement signed by the patient
  • Diagnosis of HCC confirmed
  • Diagnosis of liver disease (score F3 or F4) confirmed
  • Indication of surgical resection confirmed and validated by a specialist multidisciplinary assessment meeting of gastrointestinal oncology
  • Patient operable (no indication against anaesthesiological)
  • Resectable tumor lesion (surgical expertise)
  • Laboratory tests and endoscopy: No suspicion of severe portal hypertension with bleeding risk

Exclusion Criteria:

  • Patient not willing, at risk of default of compliance, or patient can not be monitored regularly
  • Antibiotic extended or terminated for less than 1 month, may limit the effects of taking probiotics.
  • Inflammatory Bowel Disease, which could skew the results expected by taking probiotics results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02021253
Other Study ID Numbers  ICMJE 2012/130/HP
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University Hospital, Rouen
Study Sponsor  ICMJE University Hospital, Rouen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Lilian Schwarz, MD DRCI Rouen
Principal Investigator: Emmanuel Huet, MD DRCI Rouen
PRS Account University Hospital, Rouen
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP