RISE-UP: The Effect of Riboflavin in Crohn's Disease

• Sponsor: University Medical Center Groningen (Other)
• Overall Status: Completed
• CT.gov ID: NCT02538354
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arms: 2
• Actual Duration (Months): 13
• Patients Per Site Per Month: 5.4

Study Details

Study Description

Brief Summary

This study will evaluate if suppelementation of the diet with riboflavin in Crohn's disease patients will result in an increase in the amount of F. prausnitzii.

Condition or Disease	Intervention/Treatment	Phase
Crohn Disease	Dietary Supplement: Riboflavin supplementation	N/A

Detailed Description

Rationale Recent studies show that in patients with Inflammatory Bowel Disease (IBD) a dysbiosis exists in the composition of the intestinal microbiota. In particular, the potentially pathogenic bacterium Escherichia coli (E. coli) is often more abundant in the bowel of IBD patients, and the anaerobic commensal Faecalibacterium prausnitzii (F. prausnitzii) is often reduced. This last mentioned bacteria is known to be abundant in the intestine of healthy individuals. It is known to produce butyrate, which stimulates the intestinal epithelium, and to secrete anti-inflammatory substances.

Riboflavin - also known as vitamin B2 - is required for a wide variety of cellular processes and has an important role in maintaining health in humans. In a pilot intervention with healthy volunteers it is shown that a riboflavin supplement increases the number of F. prausnitzii and results in a higher production of butyrate. In Crohn's disease patients, it is known that the amount of F. prausnitzii in the intestine is generally low. Furthermore, it is known that there is an association between the number of F. prausnitzii bacteria and the length of disease in remission.

This study will evaluate if supplementation of the diet with riboflavin in Crohn's disease patients will result in a similar increase in the amount of F. prausnitzii as in healthy volunteers. In this patient group, an increase in the number of F. prausnitzii bacteria in the bowel may result in a more favourable disease course. This will be assessed with faeces calprotectin and two questionnaires. Additionally the investigators will assess if there is any modulation by riboflavin on the other intestinal bacteria, short chain fatty acids (SCFAs) (such as butyrate), and the pH of the faeces. Finally, the effect of the riboflavin on the permeability of the gut will be evaluated with a Chroom-EDTA test, and a number of different biomarkers of permeability.

Hypothesis The hypothesis is that in Crohn's disease patients, supplementation of the diet with riboflavin results in an increase in the amount of F. prausnitzii, changes in microbial composition, increased fatty acid production, an increase in pH and a reduction of intestinal permeability. These changes might result in a more favourable disease course with less exacerbations.

Study design Prospective clinical study.

Study population and sample size In total 84 Crohn's disease patients will be included in this study, divided into two groups. Group 1 (n=42) will consist of patients with disease in remission (quiescent disease); group 2 (n=42) will consist of patients with active disease. In this study an adaptive design will be used. First 12 patients in the disease in remission group will be analysed. The methods of analysis and safety aspects will be taken into account.

Intervention Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: The Effect of Riboflavin Supplementation on Faecalibacterium Prausnitzii in Crohn's Disease
• Actual Study Start Date: Mar 1, 2016
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Apr 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Riboflavin supplementation in quiescent disease Group 1 (n=42) will consist of patients with disease in remission (quiescent disease).	Dietary Supplement: Riboflavin supplementation; Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks; Other Names: vitamin B2 supplementation
Experimental: Riboflavin supplementation in active disease Group 2 (n=42) will consist of patients with active disease.	Dietary Supplement: Riboflavin supplementation; Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks; Other Names: vitamin B2 supplementation

Outcome Measures

Primary Outcome Measures

1. F. Prausnitzii (FISH Analysis). [Different time points up to 6 weeks from start study: Day0, Day7, Day28]

   The faeces is collected at different time points before and after riboflavin supplementation. To investigate the effect of a riboflavin supplement on the number of F. prausnitzii bacteria in the faeces of active and quiescent Crohn's disease patients.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Crohn's disease patients

• Age 18-65 years

• Concomitant medication for Crohn's disease is allowed in all groups

Exclusion Criteria:

• Swallowing disorders

• Pregnancy and lactation

• Use of antibiotic drugs, probiotics (i.e.Yakult, Vifit, Activia etc) or specific prebiotic supplements in the 3 weeks prior to the riboflavin intervention

• Use of Methotrexate drugs

• Colonoscopy and colon cleansing in last 3 months

• Use of a vitamin B2 supplement, or multivitamin complexes containing vitamin B (i.e. vitamin B-complex) in the 3 weeks prior to the riboflavin intervention

• Severe Crohn's disease (HBI > 12)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Medical Center Groningen	Groningen		Netherlands	9713GZ

Sponsors and Collaborators

• University Medical Center Groningen

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 10, 2016

More Information

Publications

• Fujimoto T, Imaeda H, Takahashi K, Kasumi E, Bamba S, Fujiyama Y, Andoh A. Decreased abundance of Faecalibacterium prausnitzii in the gut microbiota of Crohn's disease. J Gastroenterol Hepatol. 2013 Apr;28(4):613-9. doi: 10.1111/jgh.12073.
• Khan MT, Duncan SH, Stams AJ, van Dijl JM, Flint HJ, Harmsen HJ. The gut anaerobe Faecalibacterium prausnitzii uses an extracellular electron shuttle to grow at oxic-anoxic interphases. ISME J. 2012 Aug;6(8):1578-85. doi: 10.1038/ismej.2012.5. Epub 2012 Feb 23.
• Louis P, Flint HJ. Diversity, metabolism and microbial ecology of butyrate-producing bacteria from the human large intestine. FEMS Microbiol Lett. 2009 May;294(1):1-8. doi: 10.1111/j.1574-6968.2009.01514.x. Epub 2009 Feb 13. Review.
• Miquel S, Martín R, Rossi O, Bermúdez-Humarán LG, Chatel JM, Sokol H, Thomas M, Wells JM, Langella P. Faecalibacterium prausnitzii and human intestinal health. Curr Opin Microbiol. 2013 Jun;16(3):255-61. doi: 10.1016/j.mib.2013.06.003. Epub 2013 Jul 3. Review.
• Sartor RB. Microbial influences in inflammatory bowel diseases. Gastroenterology. 2008 Feb;134(2):577-94. doi: 10.1053/j.gastro.2007.11.059. Review.
• Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux JJ, Blugeon S, Bridonneau C, Furet JP, Corthier G, Grangette C, Vasquez N, Pochart P, Trugnan G, Thomas G, Blottière HM, Doré J, Marteau P, Seksik P, Langella P. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16731-6. doi: 10.1073/pnas.0804812105. Epub 2008 Oct 20.
• Sokol H, Seksik P, Furet JP, Firmesse O, Nion-Larmurier I, Beaugerie L, Cosnes J, Corthier G, Marteau P, Doré J. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009 Aug;15(8):1183-9. doi: 10.1002/ibd.20903.
• Swidsinski A, Loening-Baucke V, Vaneechoutte M, Doerffel Y. Active Crohn's disease and ulcerative colitis can be specifically diagnosed and monitored based on the biostructure of the fecal flora. Inflamm Bowel Dis. 2008 Feb;14(2):147-61.
• Willing B, Halfvarson J, Dicksved J, Rosenquist M, Järnerot G, Engstrand L, Tysk C, Jansson JK. Twin studies reveal specific imbalances in the mucosa-associated microbiota of patients with ileal Crohn's disease. Inflamm Bowel Dis. 2009 May;15(5):653-60. doi: 10.1002/ibd.20783.

• Responsible Party: Prof. dr. G. Dijkstra, Prof. dr. G. Dijkstra, University Medical Center Groningen
• ClinicalTrials.gov Identifier: NCT02538354
• Other Study ID Numbers: METc 2014/291; Protocol ID
• First Posted: Sep 2, 2015
• Last Update Posted: Apr 3, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by Prof. dr. G. Dijkstra, Prof. dr. G. Dijkstra, University Medical Center Groningen: Riboflavin (vitamin B2); Faecalibacterium prausnitzii
• Additional relevant MeSH terms: Crohn Disease; Riboflavin

Study Results

Participant Flow

Arm/Group Title	Riboflavin Supplementation in Quiescent Disease	Riboflavin Supplementation in Active Disease
Arm/Group Description	Group 1 (n=42) will consist of patients with disease in remission (quiescent disease). Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks	Group 2 (n=42) will consist of patients with active disease. Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks
Period Title: Overall Study
STARTED	40	30
COMPLETED	40	30
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Riboflavin Supplementation in Quiescent Disease	Riboflavin Supplementation in Active Disease	Total
Arm/Group Description	Group 1 (n=42) will consist of patients with disease in remission (quiescent disease). Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks	Group 2 (n=42) will consist of patients with active disease. Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks	Total of all reporting groups
Overall Participants	40	30	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.2 (11.6)	38.8 (13.6)	41.9 (12.7)
Sex: Female, Male (Count of Participants)
Female	29 72.5%	19 63.3%	48 68.6%
Male	11 27.5%	11 36.7%	22 31.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	40 100%	30 100%	70 100%

Outcome Measures

1. Primary Outcome

Title	F. Prausnitzii (FISH Analysis).
Description	The faeces is collected at different time points before and after riboflavin supplementation. To investigate the effect of a riboflavin supplement on the number of F. prausnitzii bacteria in the faeces of active and quiescent Crohn's disease patients.
Time Frame	Different time points up to 6 weeks from start study: Day0, Day7, Day28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Riboflavin Supplementation in Quiescent Disease	Riboflavin Supplementation in Active Disease
Arm/Group Description	Group 1 (n=42) will consist of patients with disease in remission (quiescent disease). Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks	Group 2 (n=42) will consist of patients with active disease. Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks
Measure Participants	40	30
T0 (Mean of Day 0 and Day 7 combined)	4.53	5.07
T3 (Day 28)	6.19	5.46

Adverse Events

Time Frame	6 weeks
Adverse Event Reporting Description	No adverse events observed in this study
Arm/Group Title	Riboflavin Supplementation in Quiescent Disease		Riboflavin Supplementation in Active Disease
Arm/Group Description	Group 1 (n=42) will consist of patients with disease in remission (quiescent disease). Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks		Group 2 (n=42) will consist of patients with active disease. Riboflavin supplementation: Supplementation of the normal diet with 1 capsule of 100 mg riboflavin (vitamin B2) during three weeks
All Cause Mortality
	Riboflavin Supplementation in Quiescent Disease		Riboflavin Supplementation in Active Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/30 (0%)
Serious Adverse Events
	Riboflavin Supplementation in Quiescent Disease		Riboflavin Supplementation in Active Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Riboflavin Supplementation in Quiescent Disease		Riboflavin Supplementation in Active Disease
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.