Gluten and (Extra-)Intestinal Symptoms in NCGS

Study Overview
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Brief Summary
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The goal of this randomized, double-blind, placebo-controlled study is to investigate the effect of expectancy related to gluten consumption versus actual gluten intake on overall GI symptoms in individuals with non-coeliac gluten sensitivity (NCGS) The main questions it aims to answer are: what is the effect of consumer expectancy, related to either gluten-containing or gluten-free oat bread, on short-term (within 8 hours) overall GI symptoms in individuals with NCGS? what is the effect of actual gluten intake on short-term (within 8 hours) overall GI symptoms in individuals with NCGS Participants will be randomised into four groups: Participants with the expectation of receiving gluten-containing bread and actually receiving gluten-containing oat bread during the test day. (E+ G+) Participants with the expectation of receiving gluten-containing bread, but actually receiving gluten-free oat bread during the test day. (E+ G-) Participants with the expectation of receiving gluten-free bread but actually receiving gluten-containing oat bread during the test day. (E- G+) Participants with the expectation of receiving gluten-free bread and actually receiving gluten-free oat bread during the test day. (E- G-)

Detailed Description
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One on-site test, starting with baseline measurement (T = 0). Thereafter, subjects are told that they will receive two slices of gluten-containing bread (E+) or gluten-free bread (E-). Consequently, they receive breakfast with two slices of bread (gluten-containing (G+) or gluten-free (G-)). After breakfast, questionnaires will be completed every hour for 8 hours. After T = 4 hours, participants receive lunch with two slices of the same bread, combined with the same expectancy, that they received at breakfast. Follow-up measurements include the same questionnaires at the end of day 1 (from end of test day until they go to sleep), at the end of day 2 and at the end of day 3.

Official Title
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The Effects of Bread Consumption on Intestinal and Extra-intestinal Symptoms in Non-coeliac Gluten Sensitivity

Conditions
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Non-celiac Gluten Sensitivity

Intervention / Treatment
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* Other: Expectancy and gluten


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Develops self-reported GI symptoms within 8 hours after a single intake of gluten-containing products, without a diagnosis of an organic GI disease; Following of willing to follow a gluten-free or gluten-restricting diet (based on a gluten-free dietary compliance questionnaire of Biagi et al. (only group 2, 3 and 4 will be eligible), for at least 1 week prior to study participation and willing to continue with this throughout the study; Asymptomatic or only mildly symptomatic (overall (GI) symptom score with VAS < 30mm) while on the gluten-free diet; Willing to participate in a study in which they have to consume 4 slices of gluten-containing or gluten-free bread for breakfast and lunch during the test day; Willing and able to give written informed consent and to understand, participate and comply with the research project requirements. Exclusion Criteria: Coeliac disease; Wheat allergy; Presence of an organic GI disease (such as inflammatory bowel disease) or other disease which may interfere with NCGS symptoms (upon judgment of the physician clinical investigator); Previous major abdominal surgery or radiotherapy interfering with GI 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; Use of medication potentially influencing GI function and/or NCGS symptoms is allowed, provided that dosing has been stable for > 6 weeks before enrolment; Administration of antibiotics, probiotic or 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 diet within the study period; Any malignancy; Pregnancy or breastfeeding; Insufficient fluency of the Dutch (for Maastricht and Wageningen) or Englisch (for Leeds) language.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: E+ G+<br>Participants with the expectation of receiving gluten-containing bread and actually receiving gluten-containing oat bread during the test day. | Other: Expectancy and gluten<br>* Effect of expectancy to receive gluten and/or actual gluten intake<br>|
| Active Comparator: E+ G-<br>Participants with the expectation of receiving gluten-containing bread, but actually receiving gluten-free oat bread during the test day. | Other: Expectancy and gluten<br>* Effect of expectancy to receive gluten and/or actual gluten intake<br>|
| Active Comparator: E- G+<br>Participants with the expectation of receiving gluten-free bread but actually receiving gluten-containing oat bread during the test day. | Other: Expectancy and gluten<br>* Effect of expectancy to receive gluten and/or actual gluten intake<br>|
| Placebo Comparator: E- G-<br>Participants with the expectation of receiving gluten-free bread and actually receiving gluten-free oat bread during the test day. | Other: Expectancy and gluten<br>* Effect of expectancy to receive gluten and/or actual gluten intake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall gastrointestinal symptom score (short term) | Change from baseline, measured on a Visual Analogue Scale ranged from 0-100, in which 0 is absence of symptoms and 100 is severe symptoms. | Test day: baseline (T = 0 hours), hourly after breakfast (T = 1 hour until T = 4 hours), and hourly after lunch (T = 5 hours until T = 8 hours) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual gastrointestinal symptom scores (short term) | Change from baseline, measured on a 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. | Test day: baseline (T = 0 hours), hourly after breakfast (T = 1 hour until T = 4 hours), and hourly after lunch (T = 5 hours until T = 8 hours) | 
| Individual extra-intestinal symptom scores (short term) | Change from baseline, measured on a Visual Analogue Scale ranged from 0-100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: tiredness, headache, foggy mind | Test day: baseline (T = 0 hours), hourly after breakfast (T = 1 hour until T = 4 hours), and hourly after lunch (T = 5 hours until T = 8 hours) | 
| Average stool frequency and consistency (short term) | 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. | Test day: baseline (T = 0 hours), hourly after breakfast (T = 1 hour until T = 4 hours), and hourly after lunch (T = 5 hours until T = 8 hours) | 
| Mood (short term) | Change from baseline. Mood is measured by the Positive and Negative Affective Schedule (PANAS) questionnaire. | Test day: baseline, every hour after breakfast (T = 1 hour until T = 8 hours) | 
| Overall and individual gastrointestinal symptom score (long-term) | Change from baseline, measured on a Visual Analogue Scale ranged from 0-100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: overall gastrointestinal symtoms, abdominal pain, abdominal discomfort, belching, bloating, flatulence, diarrhoea, constipation, urge to empty bowel, fullness, nausea. | Follow-up: end of day 1 (time from end of test day (t = 8 hours) until end of that day), end of day 2, end of day 3 | 
| Individual extra-intestinal symptom scores (long term) | Change from baseline, measured on a Visual Analogue Scale ranged from 0-100, in which 0 is absence of symptoms and 100 is severe symptoms. Parameters: tiredness, headache, foggy mind | Follow-up: end of day 1 (time from end of test day (t = 8 hours) until end of that day), end of day 2, end of day 3 | 
| Average stool frequency and consistency (long term) | 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: end of day 1 (time from end of test day (t = 8 hours) until end of that day), end of day 2, end of day 3 | 
| Mood (long term) | Change from baseline. Mood is measured by the Positive and Negative Affective Schedule (PANAS) questionnaire. | Follow-up: end of day 1 (time from end of test day (t = 8 hours) until end of that day), end of day 2, end of day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Coeliac Gluten Sensitivity, NCGS, Gluten, Gastrointestinal symptoms