Prediction of Dietary Intervention Efficacy in Mild Ulcerative Colitis Patients Based on Fecal Microbiome Signatures (PREDUCTOME)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Dietary supplement: Prebiotics; Dietary supplement: Placebo

Detailed Description

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
• Enrollment (Anticipated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Erwin G Zoetendal, PhD; Phone Number: +31 (0)317- 483111; Email: erwin.zoetendal@wur.nl
• Study Contact Backup: Name: Zhuang Liu, MSc; Phone Number: +31 (0)617 659 164; Email: zhuang.liu@wur.nl

Study Locations

• Netherlands
  • Gelderland
    • Wageningen, Gelderland, Netherlands, 6708WE
      • Wageningen University
      • Contact: Erwin G Zoetendal, PhD; Phone Number: +31 (0)317- 483111; Email: erwin.zoetendal@wur.nl
      • Contact: Zhuang Liu, MSc; Phone Number: +31 (0)617 659 164; Email: zhuang.liu@wur.nl
      • Principal Investigator: Erwin G Zoetendal, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male and female subjects aged 18 to 65 years
2. Body Mass Index (BMI) between 18 and 30 kg/m2 (self-reported)
3. Ulcerative Colitis confirmed via previous endoscopy and histology
4. Mild active UC as defined by P-SCCAI score of 3 to 5 (range 0 to 19)
5. Frequent relapse (at least one exacerbation in the last two years)
6. No known allergy to any components of the study product (self-reported)
7. Signed informed consent
8. Stable UC medication defined as no switch to other medication or no dose change
9. Mobile phone on which apps (used for questionnaires) can be downloaded (iOS version 9 and newer, Android version 4.4 and newer. Phones manufactured after 2013 are usually suitable)
10. Stable dietary pattern during the study

Exclusion Criteria:

1. Any other underlying disease of the GI-tract or previous bowel surgery, except cholecystectomy and appendectomy
2. Pregnancy or intending to become pregnant during the study
3. Use of medication that can interfere with the study outcomes, as judged by the medical supervisor
4. The need for antibiotic use during the intervention period
5. Systemic antibiotics and proton pump inhibitors (except for omeprazole and pantoprazole with dosage <20 mg), prebiotic supplements, probiotic supplements four weeks prior to study start
6. Currently participating in another intervention study
7. Acquaintances of anyone in the research team

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Predicted responders with prebiotics; Predicted responders, which are defined as UC patients having a relative abundance of Bacteroidetes <=10% in their feces, will receive 6 grams of prebiotics per day.	Dietary supplement: Prebiotics; 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.
Placebo Comparator: Predicted responders with placebo; Predicted responders, which are defined as UC patients having a relative abundance of Bacteroidetes <=10% in their feces, will receive 6 grams of placebo per day.	Dietary supplement: Placebo; 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.
Experimental: Predicted non-responders with prebiotics; Predicted non-responders, which are defined as UC patients having a relative abundance of Bacteroidetes >=15% in their feces, will receive 6 grams of prebiotics per day.	Dietary supplement: Prebiotics; 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.
Placebo Comparator: Predicted non-responders with placebo; Predicted non-responders, which are defined as UC patients having a relative abundance of Bacteroidetes >=15% in their feces, will receive 6 grams of placebo per day.	Dietary supplement: Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Response at the end the intervention (T= 8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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	Change during the intervention (at T= 0, 4, and 8 weeks)
Stool frequency	Stool frequency will be measured by counting number of defecation on a daily basis for 7 days.	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.	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.	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.	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.	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.	Change during the intervention (at T= 0, 4, and 8 weeks)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Habitual dietary intake	Habitual dietary intake including energy, nutrient, and fiber intake of the last month will be assessed by a validated food frequency questionnaire (FFQ) via FFQ-tool, a web-based interface tool.	FFQ will be taken at T= 0 (baseline).
Participants demographics and characteristics	General information (e.g., sex, age, BMI, disease duration, age at diagnosis, smoking habit, UC location, type of treatment) will be collected	This information will be collected at T= 0 (baseline).

Collaborators and Investigators

• Sponsor: Wageningen University
• Collaborators: Winclove Probiotics B.V.; China Scholarship Council
• Investigators: Principal Investigator: Erwin G Zoetendal, PhD, Laboratory of Microbiology, Wageningen University

Publications and helpful links

General Publications

• Liu Z, de Vries B, Gerritsen J, Smidt H, Zoetendal EG. Microbiome-based stratification to guide dietary interventions to improve human health. Nutr Res. 2020 Oct;82:1-10. doi: 10.1016/j.nutres.2020.07.004. Epub 2020 Jul 21.
• Fassarella M, Blaak EE, Penders J, Nauta A, Smidt H, Zoetendal EG. Gut microbiome stability and resilience: elucidating the response to perturbations in order to modulate gut health. Gut. 2021 Mar;70(3):595-605. doi: 10.1136/gutjnl-2020-321747. Epub 2020 Oct 13.

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2023
• Primary Completion (Anticipated): October 1, 2024
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 11, 2022
• First Posted (Actual): October 13, 2022

Study Record Updates

• Last Update Posted (Actual): April 26, 2023
• Last Update Submitted That Met QC Criteria: April 25, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: ulcerative colitis; prediction; prebiotics; fiber intake; gut microbiome signature
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: NL79442.091.22 (Other Identifier: METC Oost Nederlands)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: As the data contains sensitive personal information researchers interested in the data can contact the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No