Effects of Different Bread Types in NCWS (BREAD)

• ClinicalTrials.gov Identifier: NCT04084470
• Recruitment Status: Completed
• First Posted: September 10, 2019
• Last Update Posted: March 28, 2023
• Sponsor: Maastricht University
• Collaborator: Wageningen University
• Information provided by (Responsible Party): Maastricht University

Tracking Information

• First Submitted Date: August 20, 2019
• First Posted Date: September 10, 2019
• Last Update Posted Date: March 28, 2023
• Actual Study Start Date: September 17, 2019
• Actual Primary Completion Date: December 20, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 1, 2021)

Overall GI symptom score [ Time Frame: At the end of day 1, 2 and 3 of the run-in period, at the end of test day 1, 2 and 3, and at the end of the last three days of each wash-out period (so the three days prior to testday 2 and 3). ]

Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms.

Original Primary Outcome Measures (submitted: September 9, 2019)

Overall GI symptom score [ Time Frame: At the end of each day of the run-in period, both intervention periods and wash-out period day 9-11. ]

Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms.

Current Secondary Outcome Measures (submitted: March 24, 2023)

• Individual Intestinal symptom scores [ Time Frame: At the end of day 1, 2 and 3 of the run-in period, at the end of test day 1, 2 and 3, and at the end of the last three days of each wash-out period (so the three days prior to testday 2 and 3). ]
  Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: abdominal pain, abdominal discomfort, belching, bloating, flatulence, diarrhoea, constipation, urge to empty bowel, fullness, nausea.
• Individual Extra-intestinal symptom scores [ Time Frame: At the end of day 1, 2 and 3 of the run-in period, at the end of test day 1, 2 and 3, and at the end of the last three days of each wash-out period (so the three days prior to testday 2 and 3). ]
  Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: tiredness, headache, joint pains, confusion, loss of coordination, skin rash.
• Average stool frequency and consistency [ Time Frame: After every stool production during day 1, 2 and 3 of the run-in period, during test day 1, 2 and 3, and during the last three days of each wash-out period (so the three days prior to testday 2 and 3). ]
  Bristol Stool Scale, a validated scale for faecal frequency and consistency, by classifying faeces into seven groups. Type 1: separate hard lumps, like nuts (hard to pass); Type 2: sausage-shaped but lumpy; Type 3: Like a sausage but with cracks on its surface; Type 4: Like a sausage or snake, smooth and soft; Type 5: Soft blobs with clear-cut edges (passed easily); Type 6: fluffy pieces with ragged edges, a mushy stool; Type 7: watery, no solid pieces / entirely liquid. Type 1-2 indicate constipation, type 3-4 are ideal stools as they are easier to pass, and type 5-7 may indicate diarrhoea and urgency.
• Follow-up: microbiota composition [ Time Frame: Follow-up measurement, within 1 year after completion of test day 3. ]
  After completion of the primary study, 5 responders (see in- and exclusion criteria) will be included for a follow-up measurement. For comparison, 5 healthy controls will be included. The participants will collect one fecal sample at home. These samples will be used to study the effect of the six different bread types on microbiota composition in an in vitro fermentation model.
• Follow-up: microbiota activity [ Time Frame: Follow-up measurement, within 1 year after completion of test day 3. ]
  After completion of the primary study, 5 responders (see in- and exclusion criteria) will be included for a follow-up measurement. For comparison, 5 healthy controls will be included. The participants will collect one fecal sample at home. These samples will be used to study the effect of the six different bread types on microbiota activity, measured by the release of microbial VOCs, in an in vitro fermentation model.

Original Secondary Outcome Measures (submitted: September 9, 2019)

• Individual Intestinal symptom scores [ Time Frame: At the end of each day of the run-in period, both intervention periods and wash-out period day 9-11. ]
  Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: abdominal pain, abdominal discomfort, belching, bloating, flatulence, diarrhoea, constipation, urge to empty bowel, fullness, nausea.
• Individual Extra-intestinal symptom scores [ Time Frame: At the end of each day of the run-in period, both intervention periods and wash-out period day 9-11. ]
  Change from baseline, measured on the Visual Analogue Scale ranged from 0 - 100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: tiredness, headache, joint pains, confusion, loss of coordination, skin rash.
• Average stool frequency and consistency [ Time Frame: After every stool production during each day of the run-in period, both intervention periods and wash-out period day 9-11. ]
  Bristol Stool Scale, a validated scale for faecal frequency and consistency, by classifying faeces into seven groups. Type 1: separate hard lumps, like nuts (hard to pass); Type 2: sausage-shaped but lumpy; Type 3: Like a sausage but with cracks on its surface; Type 4: Like a sausage or snake, smooth and soft; Type 5: Soft blobs with clear-cut edges (passed easily); Type 6: fluffy pieces with ragged edges, a mushy stool; Type 7: watery, no solid pieces / entirely liquid. Type 1-2 indicate constipation, type 3-4 are ideal stools as they are easier to pass, and type 5-7 may indicate diarrhoea and urgency.
• Microbial composition and activity [ Time Frame: Oral microbiota and faeces samples will be collected at four time-points during the study: day 4 (morning after run-in), day 7 (morning after intervention period 1), day 18 (morning after wash-out, and day 21 (morning after intervention period 2). ]
  Oral and faecal microbiota composition and functional capacity will be assessed by characterizing of the full genetic microbial content by state-of-the-art next generation sequencing. Furthermore, metabolites of saccharolytic and proteolytic fermentation will be assessed.
• Exhaled Metabolite production [ Time Frame: Exhaled air will be collected at four time-points during the study: day 4 (morning after run-in), day 7 (morning after intervention period 1), day 18 (morning after wash-out, and day 21 (morning after intervention period 2). ]
  Volatile organic compounds in exhaled air will be measure by gas chromatography time-of flight mass spectrometry (GC-tof-MS).
• Immune parameters [ Time Frame: Blood and faecal samples will be collected at four time-points during the study: day 4 (morning after run-in), day 7 (morning after intervention period 1), day 18 (morning after wash-out, and day 21 (morning after intervention period 2). ]
  Immune parameters in serum (such as CRP, TNF-a, IL-1b, IL-6, IL-8) and feaces (such as sIgA, human beta defensin 2 (HBD2), calprotectin) will be measured. Furthermore, intestinal fatty acids binding protein (iFABP) will be measured in serum, as biomarker of intestinal cell damage.

Current Other Pre-specified Outcome Measures (submitted: December 1, 2021)

• Food intake by three-day food records [ Time Frame: For 24 hours during day 1, 2 and 3 of the run-in period, during test day 1, 2 and 3, and during the last three days of each wash-out period (so the three days prior to test day 2 and 3). ]
  A three-day food record (on paper) to check for the adherence to the gluten-free diet.
• Participant characteristics in relation to NCWS [ Time Frame: Data on medical history and demographic factors will be collected during the screening visit as part of the screening process. Data on psychological factors will be collected after inclusion of subjects, before the start of the run-in period. ]
  To characterise NCWS subjects, data will be collected on medical history (e.g. surgery, GI diseases, medication use, allergies), demographic (e.g. age, gender, educational background, BMI, smoking, alcohol use) and psychosocial factors (relating to e.g. anxiety, depression, somatisation) using screening questionnaires.

Original Other Pre-specified Outcome Measures (submitted: September 9, 2019)

• Food intake by three-day food records [ Time Frame: Throughout each day of the run-in period, both intervention periods and wash-out period day 9-11. ]
  A three-day food record (on paper) to check for the adherence to the gluten-free diet.
• Participant characteristics in relation to NCGS [ Time Frame: Data on medical history and demographic factors will be collected during the screening visit as part of the screening process. Data on psychological factors will be collected after inclusion of subjects, before the start of the run-in period. ]
  To characterise NCGS subjects, data will be collected on medical history (e.g. surgery, GI diseases, medication use, allergies), demographic (e.g. age, gender, educational background, BMI, smoking, alcohol use) and psychosocial factors (relating to e.g. anxiety, depression, somatisation) using screening questionnaires.
• Oral microbiota and protein analysis [ Time Frame: Oral microbiota and faeces samples will be collected at four time-points during the study: day 4 (morning after run-in), day 7 (morning after intervention period 1), day 18 (morning after wash-out, and day 21 (morning after intervention period 2). ]
  Explorative comparison of oral microbiota with faecal microbiota. Protein analysis relates to defence proteins (including e.g. IgA, lysozyme) and will be performed in line with faecal microbiota, looking at overall microbial structure (alpha- and beta diversity indices) and specific taxa.

Descriptive Information

• Brief Title: Effects of Different Bread Types in NCWS
• Official Title: The Effects of the Different Bread Types of Fully Known Composition on Gastrointestinal Symptoms in Individuals With Non-coeliac Wheat Sensitivity.

Brief Summary

Although wheat and gluten containing food products are generally considered to be healthy, a large number of individuals in the general population reduces or limits their intake and/or replaces wheat by other grains because of possible symptoms. This non-coeliac wheat sensitivity (NCWS) is accompanied by a range of (extra-)intestinal complaints soon after consuming wheat, which improve after wheat withdrawal. Evidence for a biological mechanism and for the exact contributing compound is limited. Furthermore, the impact of grain type, bread processing and the resulting compositional changes in bread on gastrointestinal tolerability in NCWS is unclear, especially as consumed part of a typical daily human diet.

The objective of this study is to investigate the effects of well-characterised breads on (extra-)intestinal symptoms in individuals with NWGS using two double-blind randomized cross-over design (study A and B). Subjects are required to avoid any products that cause GI symptoms (e.g. wheat products) during the trial. The investigators hypothesize that grain type and processing will have a different effect on the primary outcomes.

In addition, we want to explore the in vitro effect of each bread type on gut microbiota composition and activity.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Double-blind randomized cross-over study

Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science

• Condition: Non-Coeliac Wheat Sensitivity (NCWS)

Intervention

Dietary Supplement: Different types of bread

Two studies comprising a double-blind randomized cross-over study. All subjects start with a run-in period of 3 days, thereafter they will receive three different types of bread in a randomized order for 1 day each, with a wash-out period of at least 7 days in between. Before test days 2 and 3, there is also a run-in period of three days.

Study Arms

• Active Comparator: Bread types 1, 2 and 3
  Daily consumption of 5 slices of allocated bread type for three intervention days (separated by a wash-out period of at least 7 days).
  Intervention: Dietary Supplement: Different types of bread
• Active Comparator: Bread types 4, 5 and 6
  Daily consumption of 5 slices of allocated bread type for three intervention days (separated by a wash-out period of at least 7 days).
  Intervention: Dietary Supplement: Different types of bread

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 1, 2021): 40
• Original Estimated Enrollment (submitted: September 9, 2019): 75
• Actual Study Completion Date: December 20, 2022
• Actual Primary Completion Date: December 20, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Develops of self-reported GI symptoms within 12 hours after a single intake of bread;
• Age between 18-70 years;
• Asymptomatic or only mildly symptomatic (overall) GI symptoms score with VAS < 30mm) while on the gluten-free/gluten-restricted diet;
• Must have a freezer (-18ºC) to store the study breads during the study;
• Willing and able to give written informed consent and to understand, participate and comply with the research project requirements.

Exclusion Criteria:

• Medical history of coeliac disease, wheat allergy, inflammatory bowel disease, presence of an organic gastrointestinal (GI) disease (such as inflammatory bowel disease) or other disease which may interfere with NCWS symptoms (upon judgment of the physician-clinical investigator (Dr. Keszthelyi, Gastroenterologist MUMC+));

• Previous major abdominal surgery or radiotherapy interfering with gastrointestinal function:

  • Uncomplicated appendectomy, cholecystectomy and hysterectomy allowed unless within the past 6 months;
  • Other surgery may be allowed based upon judgment of the physician-clinical investigator (Dr. Keszthelyi, Gastroenterologist MUMC+), who will decide on inor exclusion based upon the surgery applied;
• Use of medication potentially influencing gastrointestinal function and/or NCWS symptoms is allowed, provided that dosing has been stable for ≥ 1 month before enrolment;
• Administration of probiotic, prebiotic supplements, investigational drugs or participation in any scientific intervention study, which may interfere with this study (to be decided by the principle investigator), in the 14 days prior to the study;
• Excessive use of alcohol (>15 alcoholic units per week), or other drugs;
• Plan to lose weight or follow a specific weight loss diet within the study period;
• Current malignancy;
• Pregnancy or breastfeeding;
• Participation in any scientific intervention study, which may interfere with this study;
• Insufficient fluency of the Dutch language.

Follow-up measurement - inclusion criteria

• (1) NCWS subject: develops GI symptoms within 12 hours after consumption of at least one of the study breads of study A or B (+15 mm on VAS); OR (2) Healthy control (sex matched to NCWS subjects): eats bread regularly (min. 5 days per week)
• Age between 18-70 years;
• Must have a fridge (4-7ºC) to shortly store the collected faecal sample.

Follow-up measurement - exclusion criteria in addition to the criteria listed above:

• Use of antibiotics during the 6 past months prior to faecal sampling;
• Healthy controls: developing GI symptoms after consumption of bread, or following a gluten-free or wheat-free

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT04084470
• Other Study ID Numbers: NL67466.068.18; METC18-032 ( Other Identifier: METC azM/UM )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Maastricht University
• Original Responsible Party: Same as current
• Current Study Sponsor: Maastricht University
• Original Study Sponsor: Same as current
• Collaborators: Wageningen University

Investigators

• Principal Investigator: Daisy MAE Jonkers, Prof., PhD; Maastricht University

• PRS Account: Maastricht University
• Verification Date: March 2023