Clinical trial NCT02865707: Ulcerative Colitis Relapse Prevention by Prebiotics
Official title: Prevention of Ulcerative Colitis by Prebiotics: Efficacy and Protective Mechanisms
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Ulcerative Colitis
Keywords: ulcerative colitis
prebiotics
b-fructans
inulin
oligofructose
intestinal microbiota
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: University of British Columbia
First posted: 2016-08-12
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

Eligibility criteria: Inclusion Criteria:

* Patients with Ulcerative colitis (UC) with confirmed diagnosis by histology and endoscopy.
* Currently in clinical remission defined as total Mayo score of ≤ 2 and endoscopic score of 0 or 1) who have experienced at least one flare in the past 18 months.
* On stable doses of oral 5-ASA for 2 weeks and/or a stable doses of azathioprine and/or anti-tumor necrosis factor (anti-TNF) biologics for 2 months
* Colonic involvement of \>15 cm from the anal verge.
* Ability to give valid informed consent
* For females of child bearing potential, a negative pregnancy test and an agreement to use appropriate birth control over the study period.

Exclusion Criteria:

* Crohn's disease, indetermined colitis or infectious colitis.
* Active UC, (total Mayo score of ≥ 3)
* Taking prednisone (or steroid equivalent) within 1 month of enrollment
* Used topical 5-ASA or steroids within 2 weeks of enrollment
* Using immunosuppressive treatments of 6-mercaptopurine or methotrexate
* Used antibiotics within 2 months
* Used anti-diarreal agents with the previous 3 days
* Pregnancy or lactation
* Significant chronic disorders such as severe cardiac disease, significant renal failure, severe pulmonary disease (need for oxygen)
* Active gastrointestinal infection
* Severe psychiatric disorder
* Not able to consent to the study.

Primary outcomes:
measure: Prevention of relapse
timeFrame: 6 months
Secondary outcomes:
measure: Time to relapse
timeFrame: 6 months
measure: Patient compliance
timeFrame: 3 and 6 month
measure: Patient tolerability
timeFrame: 3 and 6 month
measure: Changes in endoscopic disease activity inflammation
timeFrame: 0 and 6 month
measure: Changes in fecal calprotectin
timeFrame: 0, 1, 3 and 6 month
measure: Changes in partial Mayo score
timeFrame: 0 and 6 month
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
Study officials:
affiliation: University of Alberta
name: Levinus A Dieleman, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Armstrong HK, Bording-Jorgensen M, Santer DM, Zhang Z, Valcheva R, Rieger AM, Sung-Ho Kim J, Dijk SI, Mahmood R, Ogungbola O, Jovel J, Moreau F, Gorman H, Dickner R, Jerasi J, Mander IK, Lafleur D, Cheng C, Petrova A, Jeanson TL, Mason A, Sergi CM, Levine A, Chadee K, Armstrong D, Rauscher S, Bernstein CN, Carroll MW, Huynh HQ, Walter J, Madsen KL, Dieleman LA, Wine E. Unfermented beta-fructan Fibers Fuel Inflammation in Select Inflammatory Bowel Disease Patients. Gastroenterology. 2023 Feb;164(2):228-240. doi: 10.1053/j.gastro.2022.09.034. Epub 2022 Sep 29.