Effects of Different Bread Types in NCWS

Study Overview
=================
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.

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

Conditions
-----------------
Non-Coeliac Wheat Sensitivity (NCWS)

Intervention / Treatment
-----------------
* Dietary Supplement: Different types of bread


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-blind randomized cross-over study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bread types 1, 2 and 3<br>Daily consumption of 5 slices of allocated bread type for three intervention days (separated by a wash-out period of at least 7 days). | Dietary Supplement: Different types of bread<br>* 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.<br>|
| Active Comparator: Bread types 4, 5 and 6<br>Daily consumption of 5 slices of allocated bread type for three intervention days (separated by a wash-out period of at least 7 days). | Dietary Supplement: Different types of bread<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall GI symptom score | 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. | 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). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual Intestinal symptom scores | 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. | 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). | 
| Individual Extra-intestinal symptom scores | 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. | 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). | 
| Average stool frequency and consistency | 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. | 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). | 
| Follow-up: microbiota composition | 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 measurement, within 1 year after completion of test day 3. | 
| Follow-up: microbiota activity | 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. | Follow-up measurement, within 1 year after completion of test day 3. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-Coeliac Wheat Sensitivity, Wheat Sensitivity, Bread, Wheat, Gastrointestinal symptoms