Ulcerative Colitis Relapse Prevention by Prebiotics
Condition: Ulcerative Colitis
MeSH terms: Colitis; Colitis, Ulcerative; Ulcer
Study type: Interventional

Summary: 
      Ulcerative colitis (UC) is a relapsing chronic intestinal inflammation with no existing cure,
      that affects over 300 per 100.000 Canadians, the highest prevalence in the world. The
      standard drug therapies are expensive and potentially toxic, and mostly directed against the
      chronic inflammatory process. UC is the result of a dysbiosis between disease-inducing and
      protective intestinal bacteria in a genetically susceptible host. Non-digestible dietary
      carbohydrates (NDC) stimulate the growth of protective endogenous intestinal bacteria which
      ferment them into short-chain fatty acids (SCFA), some of the latter with natural
      anti-inflammatory properties, and are called prebiotics. The investigator was the first to
      report that oral intake of NDC, the dietary β-fructans inulin plus fructo-oligosaccharides
      (FOS), reduced colitis in a genetically-induced rat colitis model. Both inulin and FOS
      reduced colitis, each NDC modifying specific luminal microbiota. A small trial with the same
      mixture of NDC in patients with active UC relapsing on oral 5-aminosalicylic acid (5-ASA)
      showed a dose-dependent clinical response, confirming the translational potential of this NDC
      mixture.

      The investigators propose a randomized placebo-controlled trial to assess if inulin plus FOS
      can also prevent such relapses in UC patients with inactive disease on stable maintenance
      drugs. Primary hypothesis is that inulin plus FOS is effective adjunct therapy to standard
      drugs for maintaining clinical remission. The second hypothesis is that the colonic
      microflora and its metabolic function, altered by inulin plus FOS, or not, mediate protection
      or relapse in UC. The longitudinal design of this maintenance prevention study and by
      serially collecting colon biopsies, stool, serum and urine within the same patient before a
      relapse (inflammation) occurs, would enable to identify unique changes in the intestinal
      microbiota, their metabolic functions and also assess effects on host-immune response that
      are associated with remission or before a relapse occurs during treatment with beta-fructans,
      or not.
    

Detailed description: 
      Objectives: Based on the efficacy of inulin plus FOS shown in experimental colitis as well as
      their ability to improve active human UC the investigators propose double-blind placebo
      controlled study using Synergy1, a 1:1 FOS/ inulin mixture, in patients in clinical remission
      of UC. The specific aims of this study are as follow:

        1. To determine if β-fructans are effective in maintaining clinical remission in UC
           patients.

        2. To examine the mechanisms of action of β-fructans on the intestinal microbiota
           composition and function and host immune response of these patients.

      It is hypothesized that β-fructans will prolong remission in UC patients with inactive
      disease maintained on standard drug therapy and that the prebiotics beneficial effect is
      associated with enhanced colonic energy homeostasis as a result of specific stimulation of
      butyrate- and/ or other SCFA-producing microorganisms combined with improved host mucosal
      energy and inflammation regulation.

      The proposed trial

      Trial Design: A double blind placebo controlled clinical trial

      Intervention and duration of treatment: All patients in the treatment group will receive
      chicory-derived β-fructans inulin plus FOS (1:1) ("Synergy1") for 6 months. Synergy1 will be
      administered as 7.5 gram dose twice a day as a pre-packaged powder added to meals and
      provided by Beneo-Orafti. This 15 gram daily prebiotic dose was found to be most effective in
      treating mild to moderately active UC in the investigator's previous pilot study. Patients in
      the placebo group will receive non-fermentable maltodextrin with a similar appearance, dosage
      and frequency as β-fructans. Patients that completed the 6 months treatment period will be
      monitored for disease related symptoms for additional 6 months.

      Co-Intervention: Participants will continue at standard maintenance therapy for the duration
      of the trial. Participants will be asked to maintain their regular diet. This will be
      confirmed by having subjects complete the Food Frequency Questionnaire and assessing dietary
      intake at 0 and 6 months of the study, or at relapse, using online system. Compliance will be
      assessed by counts of study agent packages and by metabolomic analysis of participants serum
      and urine.

      Specimen Samples: Fecal samples will be collected for fecal calprotectin (FC) and microbiota
      analysis at 0, 1, 3, 6 and 12 months, or at relapse. Colon biopsies will be collected between
      15-20 cm from the anus for host mucosal response (4 biopsies), microbiota studies (4
      biopsies) and histology (2 biopsies) at the start, and at 6 months, or at relapse. Urine and
      blood/serum will be collected for metabolomics analysis at 0, 1, 3 and 6 month of treatment,
      or at relapse. Colonic luminal washes will be collected at the start and at 6 months or at
      relapse during the sigmoidoscopy exam.

      Sample Size: Ninety patients, 45 in each arm, will be needed to detect a difference of 30 %
      in the proportion of UC patients with clinical recurrence by 6 months with a power of 80%
      using a two-sided p=0.05 level test. An anticipated dropout rate for this trial will be 10%,
      based on previous maintenance trials, therefore the overall sample size for this trial will
      be 100 patients.

      Outcomes:

      Primary Outcome: The proportion of patients with relapse over 6 months. Relapse is defined as
      an increase of Mayo score of 3 or more with an endoscopy grade equal to or more than 2, and
      rectal bleeding for at least 3 days. The relapse rate in the prebiotic-treated group at 6
      month will be compared to the relapse rate in the placebo group.

      Secondary outcomes: 1) Time to relapse. 2) Patient compliance and tolerability. Compliance
      will be assessed as a ratio of packages (used) divided by the total packages dispensed over 6
      months. Tolerability will be assessed by a validated questionnaire by Casellas et al on
      adverse effects such as bloating and flatulence, compliance by package, pill counting and
      metabolomic analysis at 3 and 6 months, or at relapse. 3) Intestinal inflammation (measured
      by fecal calprotectin) at baseline and months 1, 3 and 6, or at relapse. 4) Microscopic
      inflammation scores (0 and 6 months, or at relapse)

      Basic science parameters: 1) Colonic biopsies for cytokine measurement, butyrate transporters
      and oxidation pathway and Mucin 2 (MUC2) mRNA expression analysis, histological assessment
      and characterization and quantification of the mucosa-associated microbiota; 2) Stool and
      urine for assessment of fecal calprotectin concentrations, the luminal microbiota and its
      metabolic products using pyrosequencing, quantitative PCR (qPCR) and gas chromatography (GC)
      and nuclear magnetic resonance (NMR); 3) Blood/serum for metabolomic analysis with GC and
      NMR; 4) colonic luminal wastes for assessing the Immunoglobulin G (IgG) associated
      microbiota.
    

Intervention name(s): Synergy-1; Maltodextrin
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Synergy-1 is chicory-derived β-fructans inulin plus FOS (1:1).; Maltodextrin is carbohydrate adsorbed in the small bowel.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: ulcerative colitis; prebiotics; b-fructans; inulin; oligofructose; intestinal microbiota