A Prospective, Placebo Controlled, Double-Blind, Cross-over Study on the Effects of a Probiotic Preparation (VSL#3) on Metabolic Profile, Intestinal Permeability, Microbiota, Cytokines and Chemokines Expression and Other Inflammatory Markers in Pediatric Patients With Crohn's Disease

NCT01632462 | Unknown Phase 4 DMC

• 1 other identifier: 06-2012
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Background VSL#3 has been reported as an effective adjuvant therapy both in inducing and maintaining remission in pediatric patients affected by Ulcerative Colitis. In addition, it has been shown that VSL#3 is able to modulates barrier function, intestinal permeability, and innate host functions, which if altered, could have a profound impact on the state of colitis. However it is still unclear how VSL#3-induced changes in microbial composition affect the status of intestinal inflammation and no study have investigated the efficacy of VSL#3 in the maintenance of remission in pediatric patients with Crohn's disease (CD). Objectives The purpose of this study will be to evaluate the effect of a probiotic formulation, VSL#3, versus placebo, on metabolic profile, intestinal permeability, microbiota, cytokines and chemokines expression in pediatric patients with CD in remission of disease. In addition, the efficacy of VSL#3 on the maintenance of remission will be assessed and the safety and the tolerability of the probiotic formula will be evaluated. Methods This investigation will be a prospective, multicenter, randomized, double-blind, placebo-controlled, cross-over trial. The study will include 50 children affected by CD in remission of disease, as defined by a PCDAI \< 10, under treatment with Azathioprine associated or not to 5-ASA and will be articulated in 6 months as follows. All children will be randomised to a treatment group receiving for 2 months either 1-2 packet containing 900 billion bacteria/day of VSL#3 according to their weight, and a group receiving the placebo drug. Assignment to therapy or placebo will be determined according to a computer-generated randomization scheme. At the completion of the 8 weeks, a "wash-out" period of 6 weeks will be done, when no preparation will be administered. Then each patient will be switched to the other group and followed likewise for further 8 weeks. All patients will continue regular medications throughout the study period. A group of 10 volunteer healthy children, comparable in age and sex, will be used as reference group for the analysis of metabolic profile. Patients will be assessed clinically at baseline and every 8 weeks until the completion of the study, at 24 weeks or at the time of relapse. At every visit data will be collected including patient questionnaires regarding disease activity (stool frequency, stool consistency, hematochezia, abdominal pain, extraintestinal manifestations of disease, and overall patient functioning). Additional information collected at the first visit included demographic data, family history, and symptom onset. Physical examination will be performed at each visit by a paediatrician and included an abdominal examination and examination for extraintestinal manifestations of CD. Routine blood tests for CD, cellobiose/mannitol small intestinal permeability study, stool cultures, stool calprotectin, will be performed at every visit and/or at the time of relapse. Urine will be collected for the analysis of metabolic profile with mono and bi-dimensional high-resolution 1H NMR spectroscopy. PCDAI and a physician's global assessment will be used to measure disease activity. At baseline and at 24 weeks the patients will undergo ileocolonoscopy to evaluate and endoscopic and histological activity of disease. Evaluation of microbiota on biopsies and stool samples will be performed at the time of ileocolonoscopies using Fluorescence In Situ Hybridization. Colon biopsies cultures will be performed in order to evaluate cytokines and chemokines patterns by multiplex assay. Additional data will be collected during the study regarding the safety and tolerability of therapy with VSL #3. Statistical analysis will be performed using SPSS version 15 (SPSS Inc, Chicago, Illinois, USA). Variables will be screened for their distribution and appropriate parametric or non parametric tests will be adopted as required. Cross-tabulations will be evaluated by using the Fisher test and χ2test. Statistical significance will be predetermined as P \< 0.05. Expected results The investigators expect to find profound alterations in metabolic profiles, intestinal permeability, microbiota, cytokines and chemokine patterns of patients affected by CD. The administration of VSL#3 is expected to ameliorate all these alterations eventually identified. From a clinical point of view the effects of VSL#3 could be translated in prolonged clinical remission maintenance, offering a new therapeutic tool in the treatment of CD.

Conditions

Crohn's Disease

Keywords

Crohn's disease; VSL#3; probiotics; metabolic profile

Outcome Measures

Primary Outcomes (1)

• to evaluate the effect of a probiotic formulation, VSL#3, versus placebo, on metabolic profile, intestinal permeability, microbiota, cytokines and chemokines expression and other inflammatory markers in pediatric patients with Crohn's Disease

  Evaluation of metabolic profile, intestinal permeability, microbiota, cytokines and chemokines expression and other inflammatory markers in pediatric patients with Crohn's before and after the exposure to VSL3 to underline any differences

  22 weeks from the enrollment

Secondary Outcomes (2)

• To determine the effect on Pediatric Crohn Disease Activity Index (PCDAI);

  8, 14, 22 weeks from the enrollment

• to determine the time till flare of CD pediatric patients on VSL#3 compared to placebo.

  8, 14, 22 weeks from the enrollment

Study Arms (2)

VSL#3 arm

ACTIVE COMPARATOR

15 patients with a diagnosis of Crohn's disease will be exposed to VSL#3 for 8 weeks

Drug: VSL#3

placebo group

PLACEBO COMPARATOR

15 patients affected by Crohn's disease will be exposed to a placebo for 8 weeks

Drug: VSL#3

Interventions

VSL#3 DRUG

This investigation will be a randomized, double-blind, placebo-controlled, cross-over trial. The study will include 30 children with CD and will be articulated in 6 months as follows. These children will be randomised to a treatment group receiving for 2 months either 1-2 packet containing 900 billion bacteria/day of VSL#3 according to their weight, and a group receiving the placebo drug. Assignment to therapy or placebo will be determined according to a computer-generated randomization scheme.. At the completion of the 8 weeks, a "wash-out" period of 6 weeks will be done, when no preparation will be administered. Then each patient will be switched to the other group and followed likewise for further 8 weeks.

VSL#3 arm; placebo group

Eligibility Criteria

• Age: 5 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• diagnosis of CD as defined by clinical, radiological, histological and endoscopic criteria with negative stool culture
• Males and Females ages 5-17 years
• Subjects should have CD in remission as defined by a PCDAI \< 10
• Absence of extraintestinal manifestations
• Patients receiving the following treatment:
• Azathioprine: if the dose remained constant for 8 weeks prior to the screening visit and had been used continuously for 12 weeks before screening associated or not to 5ASA: if the dose remained constant for 4 weeks before the screening visit and had been used continuously for 8 weeks before screening
• Written informed consent by parents

You may not qualify if:

• Patients with Ulcerative Colitis (UC)
• Subjects with documented intestinal stricture, stenosis, obstruction, fistula, abscess, ileostomy
• Patients with perianal or active CD
• Treatment with anti-TNFα, ciprofloxacin, metronidazole, systemic corticosteroids, infliximab within 12 weeks of the start of the trial
• Patients with systemic or intestinal infection
• Renal, hepatic, haematological, pulmonary, cardiac, neurologic or cerebral diseases
• Probiotic use in the previous 2 months
• Inability or unwillingness to give an informed consent
• Subjects who require outpatient antibiotic therapy.
• Patients who require surgery for complications related to CD.
• Concurrent participation in an investigational drug trial
• Documented history of allergic reaction to Lactobacillus or other probiotic compound
• Use of Lactobacillus, Bifidobacterium, Enterococcus, Saccharomyces, or any other probiotic bacterial supplement within the past 10 days
• History of endocarditis, rheumatic valvular disease, congenital cardiac malformations, or cardiac surgery
• Presence of any other significant medical condition

Sponsors & Collaborators

• Federico II University: lead

Study Sites (1)

University of Naples "Federico II"

Naples, Italy, 80131, Italy

RECRUITING

Related Publications (11)

• Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, Kastelein RA. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007 Jun;132(7):2359-70. doi: 10.1053/j.gastro.2007.03.104. Epub 2007 Apr 13.

  PMID: 17570211 BACKGROUND

• Sartor RB. The influence of normal microbial flora on the development of chronic mucosal inflammation. Res Immunol. 1997 Oct-Dec;148(8-9):567-76. doi: 10.1016/s0923-2494(98)80151-x. No abstract available.

  PMID: 9588836 BACKGROUND

• Frank DN, St Amand AL, Feldman RA, Boedeker EC, Harpaz N, Pace NR. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13780-5. doi: 10.1073/pnas.0706625104. Epub 2007 Aug 15.

  PMID: 17699621 BACKGROUND

• Visekruna A, Joeris T, Schmidt N, Lawrenz M, Ritz JP, Buhr HJ, Steinhoff U. Comparative expression analysis and characterization of 20S proteasomes in human intestinal tissues: The proteasome pattern as diagnostic tool for IBD patients. Inflamm Bowel Dis. 2009 Apr;15(4):526-33. doi: 10.1002/ibd.20805.

  PMID: 19067411 BACKGROUND

• Pagnini C, Saeed R, Bamias G, Arseneau KO, Pizarro TT, Cominelli F. Probiotics promote gut health through stimulation of epithelial innate immunity. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):454-9. doi: 10.1073/pnas.0910307107. Epub 2009 Dec 14.

  PMID: 20018654 BACKGROUND

• Di Giacinto C, Marinaro M, Sanchez M, Strober W, Boirivant M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells. J Immunol. 2005 Mar 15;174(6):3237-46. doi: 10.4049/jimmunol.174.6.3237.

  PMID: 15749854 BACKGROUND

• Round JL, Mazmanian SK. The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol. 2009 May;9(5):313-23. doi: 10.1038/nri2515.

  PMID: 19343057 BACKGROUND

• Geddes K, Philpott DJ. A new role for intestinal alkaline phosphatase in gut barrier maintenance. Gastroenterology. 2008 Jul;135(1):8-12. doi: 10.1053/j.gastro.2008.06.006. Epub 2008 Jun 10. No abstract available.

  PMID: 18549817 BACKGROUND

• Reiff C, Delday M, Rucklidge G, Reid M, Duncan G, Wohlgemuth S, Hormannsperger G, Loh G, Blaut M, Collie-Duguid E, Haller D, Kelly D. Balancing inflammatory, lipid, and xenobiotic signaling pathways by VSL#3, a biotherapeutic agent, in the treatment of inflammatory bowel disease. Inflamm Bowel Dis. 2009 Nov;15(11):1721-36. doi: 10.1002/ibd.20999.

  PMID: 19639558 BACKGROUND

• Uronis JM, Arthur JC, Keku T, Fodor A, Carroll IM, Cruz ML, Appleyard CB, Jobin C. Gut microbial diversity is reduced by the probiotic VSL#3 and correlates with decreased TNBS-induced colitis. Inflamm Bowel Dis. 2011 Jan;17(1):289-97. doi: 10.1002/ibd.21366.

  PMID: 20564535 BACKGROUND

• Hyams JS, Ferry GD, Mandel FS, Gryboski JD, Kibort PM, Kirschner BS, Griffiths AM, Katz AJ, Grand RJ, Boyle JT, et al. Development and validation of a pediatric Crohn's disease activity index. J Pediatr Gastroenterol Nutr. 1991 May;12(4):439-47.

  PMID: 1678008 BACKGROUND

MeSH Terms

Conditions

Crohn Disease

Condition Hierarchy (Ancestors)

Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Study Officials

• Erasmo Miele, Assistant Professor

  Federico II University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Erasmo Miele, Assistant professor

CONTACT

00390817464565; erasmo.miele@unina.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: June 25, 2012
• First Posted: July 3, 2012
• Study Start: September 1, 2012
• Primary Completion: December 1, 2014
• Study Completion: February 1, 2015
• Last Updated: August 12, 2014

Record last verified: 2014-08

Locations

IT (1)