Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT04804046 |
| Other study ID # |
Pro00092967 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
July 15, 2021 |
| Est. completion date |
December 31, 2023 |
Study information
| Verified date |
January 2024 |
| Source |
University of Alberta |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Crohn's disease (CD) is a lifelong incurable condition that causes inflammation of the
intestinal tract of humans. The exact cause of CD is unknown, but genetics, diet, and the gut
microbiome are all thought to play a major role. Many patients with CD will require surgery
to remove affected portions of the gut, with ileocecal resections being the most common
procedure performed. Regrettably, there is up to an 85% chance that disease returns to the
surgical site. Strong immune suppressive medications may help to prevent disease relapse.
However, patients are then at risk of serious side effects. Currently, no ideal post-op care
exists for CD patients.
This study aims to assess whether a post-op synbiotic therapy (i.e. probiotics plus dietary
fiber) prevents disease relapse in participants with CD. To test this, participants will
consume probiotics (strains of bifidobacteria) before their surgery and then probiotics plus
fiber supplements after surgery. Probiotics are live bacteria that have been shown to reduce
inflammation of the gut. Fiber is given after surgery to help promote beneficial bacterial
taxa and prevent less favorable bacterial taxa from triggering CD relapse. Patients will take
the supplements for 6 months following surgery. They will be seen monthly to assess the
effects of treatment on quality of life, symptoms of disease recurrence, inflammatory
markers, and the gut microbiome. All patients will also undergo a colonoscopy at the end of
the study to check for endoscopic reoccurrence.
Description:
Crohn's disease (CD) is characterized by chronic intestinal inflammation and commonly
involves the ileocecal region. Due to disease complications, many patients with CD require an
ileocecal resection (ICR). However, disease often recurs postoperatively at the surgical
anastomosis, with endoscopic recurrence rates as high as 85%. While the immunosuppressant
infliximab has been shown to reduce endoscopic disease recurrence, it was not shown to
prevent clinical relapse. The timing of infliximab treatment might be critical, as starting
infliximab immediately after surgery rather than at the time of post-surgical recurrence
resulted in 1-year remission rates of 92% and 57%, respectively. Currently, no ideal
postoperative care exists for patients with CD. Thus, new approaches are required.
The gut microbiome has long been thought to play a causative role in the high rates of CD
recurrence following surgical resection. Immediately following ICR, a state of inflammation
and oxidative stress promotes aerotolerant microbes at the expense of beneficial short-chain
fatty acid (SCFA)-producing anaerobes. The mucosal microbial composition in CD patients at
the time of surgery is predictive of future disease relapse. Specifically, patients with a
dominance of SCFA-producing anaerobic bacteria in the ileal mucosa at the time of surgical
resection are more likely to remain in remission compared with patients which have a
dominance of aerotolerant bacteria. Nutritional adjuncts based on probiotics or prebiotics
could be applied to shift gut microbial imbalances towards SCFA-producers.
Though research is limited, probiotics containing bifidobacteria but not lactobacilli have
been shown to lessen mucosal inflammation and recurrence rates when provided immediately post
ICR. In a previous clinical trial, it was found that patients with CD that started the
probiotic VSL#3 (4 Lactobacillus; 3 Bifidobacterium; 1 Streptococcus strains) immediately
post surgery had reduced mucosal inflammatory cytokines and lower recurrence rates when
compared to patients that started VSL#3 at 3-months post surgery. A smaller trial using VSL#3
in combination with antibiotic treatment also showed lower rates of endoscopic recurrence at
3- and 12-months following surgery. These results suggest that probiotic composition and
treatment timing are critical for efficacy. While synergy between probiotics and prebiotics
might improve clinical effects, the efficacy of synergistic synbiotics remains unknown. The
aims of this study are the following:
AIM 1. Perform a parallel two-arm, randomized controlled exploratory trial in CD patients
undergoing ICR to determine the safety and tolerability of a synbiotic treatment.
This is a pilot study in patients with CD undergoing ileocecal resection to evaluate the
feasibility of supplementation with a synbiotic preparation that contains a mixture of
resistant starch type 2 (HiMaize 260; Ingredion), arabinoxylan (Naxus; Bioactive), and
galactooligosaccharide (Vivinal; FrieslandCampina) (24g/d) fibers plus probiotic bacteria
(Bifidobacterium longum spp. longum R0175, Bifidobacterium animalis spp. Lafti B94,
Bifidobacterium bifidum R0071; Lallemand Health Solutions) (3x10^9 CFU/d). Participants will
be given the probiotics 2 days prior to surgery and then the synbiotic will both be given 7
days after surgery and will be consumed daily for 6 months. Digestible maltodextrin will be
used as a placebo control (Maltodextrin GLOBE Plus 15; Ingredion). A total of 36 volunteers
will be enrolled, stratified by sex, and randomized to one of 2 groups via computer-generated
numbers, as well as blinded to their group allocation to reduce bias. Safety and tolerability
of synbiotic (primary outcome) will be determined by the percentage of participants who
experience treatment emergent adverse events and serious adverse events. Symptom and quality
of life questionnaires will also be used to evaluate tolerance.
AIM 2. Determine if synbiotic therapy attenuates mucosal and systemic inflammation and
reduces rates of disease relapse.
Each month, clinical recurrence will be evaluated by Harvey Bradshaw Index and C-reactive
protein, serum cytokines (TNF-α, IL-6, IL-8, and IL-10), intestinal barrier markers (LPS,
LPS-binding protein, and zonulin), and fecal calprotectin levels will be measured. At
6-months, endoscopic recurrence will be determined by Rutgeerts Index and biopsies will be
taken for the assessment of mucosal inflammation.
AIM 3. Evaluate the impact on compositional and functional features of the fecal microbiota
and to characterize associations between clinical and microbial outcomes.
Fecal samples will be collected each month for the characterization of the microbiota by 16S
rRNA gene sequencing. Fecal concentrations of SCFAs and bile acids will also be determined as
functional measures of the gut microbiota. Associations between clinical outcomes and
microbiota features will be assessed to identify signatures that predict the synbiotic
impact.
