A double-blind randomized placebo-controlled parallel trial with two intervention arms and two placebo arms and a period of eight intervention weeks to validate the prediction that prebiotics could induce a higher response in mild UC patients with certain fecal microbiome signatures.
Rationale: Ulcerative colitis (UC) patients respond differently to treatments/interventions (e.g. diet/fecal microbiota transplantation), but the reason for this individual specificity remains unknown. The investigators hypothesize that the baseline fecal microbiota composition determines the efficacy of a treatment/intervention, and potential responders, i.e. patients showing symptoms improvement after treatment, can be predicted based on fecal microbiota composition. Objective: The primary objective is to validate the prediction that prebiotics intervention boosts butyrate production and thereby induces a higher response (lower mean Patient Simple Clinical Colitis Activity Index (P-SCCAI) score) in mild UC patients with low intestinal Bacteroidetes levels (predicted responders), but not in those with high intestinal Bacteroidetes levels (predicted non-responders) at T = 8 weeks. The secondary objectives are to study the effects of prebiotics intervention on disease activity over time (T = 0, 4, 8, 12 and 60 weeks), mucosal inflammation, gastro-intestinal (GI) complaints, stool consistency, stool frequency, fecal microbiota composition, fecal short-chain fatty acids concentrations, quality of life, number of participants with increased or decreased medication use, and incidence of adverse events in mild UC patients. Study design: This study is a four-arm double-blind randomized placebo-controlled parallel trial. It consists of a screening stage in which mild UC patients will be assigned to be predicted responders or predicted non-responders based on fecal Bacteroidetes levels. Afterwards the predicted responders and non-responders will be assigned to either the prebiotics group (arm 1 and 3) or placebo group (arm 2 and 4). Study population: Adult subjects aged 18-65 years and body mass index 18-30 kg/m2 with mild UC defined by P-SCCAI (3-5 points in a 19-point scale), with at least one relapse in the last two years. Intervention: An 8-week intervention period with four parallel arms: 1) predicted responders with prebiotics treatment (acacia gum, partially hydrolyzed guar gum, and resistant starch), 2) predicted responders with placebo (maltodextrin and corn starch), 3) predicted non-responders with prebiotics treatment, 4) predicted non-responders with placebo, during which the study participants consume the respective supplement (3 grams, twice daily). Main study parameters/endpoints: The main parameter is the response (mean P-SCCAI score) between arms at T = 8 weeks. The secondary parameters are the disease activity over time at T = 0, 4, 8, 12, and 60 weeks, mucosal inflammation (fecal calprotectin), gastro-intestinal (GI) complaints, stool consistency, stool frequency, fecal microbiota composition, fecal short-chain fatty acids concentrations, health-related quality of life, number of participants with increased or decreased medication use, and incidence of adverse events.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
The prebiotics consists of three non-digestible carbohydrates (40% acacia gum, 20% partially hydrolyzed guar gum, and 40% resistant starch). During the 8-week intervention, two sachets (3 g per sachet) will be consumed per day, one in the morning and one in the evening.
The placebo consists of two digestible carbohydrates (20% maltodextrin and 80% corn starch). During the 8-week intervention, two sachets (3 g per sachet) will be consumed per day, one in the morning and one in the evening.
Wageningen University
Wageningen, Gelderland, Netherlands
Response between arms at T = 8 weeks
Within each arm, response will be determined by the mean Patient Simple Clinical Colitis Activity Index (P-SCAAI) score on a nineteen-point scale (from "0: no symptoms" to "19: severest symptom"). It refers to disease activity during the previous week, with higher scores representing worse disease symptoms.
Time frame: Response at the end the intervention (T= 8 weeks)
Disease activity over time (T= 0, 4, 8, 12, and 60 weeks)
Disease activity will be determined by the Patient Simple Clinical Colitis Activity Index (P-SCAAI) score on a nineteen-point scale (from "0: no symptoms" to "19: severest symptom"). With P-SCCAI score \<= 2 being regarded as clinical remission, and a decrease in the P-SCCAI score by more than two points from baseline being regarded as clinical response. Comparisons will be made between groups as well as within subjects over time.
Time frame: Disease activity during and after the intervention (at T= 0, 4, 8, 12, and 60 weeks)
Mucosal inflammation
Mucosal inflammation will be determined by the fecal calprotectin level, which is a biomarker of inflammation and disease activity.
Time frame: Change during and after the intervention (at T= 0, 8, 12, and 60 weeks)
GI complaints
The GI complaints will be assessed by the (gastrointestinal symptom rating scale) GSRS questionnaire, which has a seven-point graded scale where 1 represents the absence of troublesome symptoms and 7 represents very troublesome symptoms.
Time frame: Change during the intervention (at T= 0, 4, and 8 weeks)
Stool consistency
Stool consistency will be measured using the Bristol Stool Form Scale (7-point scale from 1=hard to 7=diarrhea) on a daily basis for 7 days
Time frame: Change during the intervention (at T= 0, 4, and 8 weeks)
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Stool frequency
Stool frequency will be measured by counting number of defecation on a daily basis for 7 days.
Time frame: Change during the intervention (at T= 0, 4, and 8 weeks)]
Fecal microbiota composition
Fecal microbiota composition will be determined by 16S rRNA gene sequencing.
Time frame: Change during and after the intervention (at T= 0, 8, 12, and 60 weeks)
Fecal short-chain fatty acids concentrations
Fecal short-chain fatty acids concentrations will be determined by HPLC.
Time frame: Change during and after the intervention (at T= 0, 8, 12, and 60 weeks)
Health-related quality of life
Health-related quality of life will be assessed by short inflammatory bowel disease questionnaire (SIBDQ) with a seven-point graded scale where 1 represents very troublesome symptoms and 7 represents the absence of troublesome symptoms.
Time frame: Change during the intervention (at T= 0, 4, and 8 weeks)
Number of participants with increased or decreased medication use
It consists of the current medication use (e.g., aminosalicylates, corticosteroids, immunosuppressive agents, antimicrobial agents, and inhibitors of tumour necrosis factor-alpha (TNF- α)) with a downgrade meaning improvement and an upgrade meaning worsening of UC.
Time frame: Change during and after the intervention (at T= 0, 4, 8, 12, and 60 weeks)
Incidence of adverse events
Incidence of adverse events will be monitored by patient record and diary, these include all relapse-relevant information, including the need for systemic steroids, hospitalization, and surgery.
Time frame: Change during the intervention (at T= 0, 4, and 8 weeks)