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Trial registered on ANZCTR


Registration number
ACTRN12620001030965
Ethics application status
Approved
Date submitted
17/06/2020
Date registered
12/10/2020
Date last updated
31/01/2022
Date data sharing statement initially provided
12/10/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Wheat sensitivity and functional dyspepsia dietary trial and challenge protocol
Scientific title
Wheat sensitivity and functional dyspepsia: A pilot, double blind, randomized placebo-controlled dietary crossover trial with novel challenge protocol
Secondary ID [1] 301538 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Functional dyspepsia 317899 0
Non-coeliac wheat sensitivity 317900 0
Condition category
Condition code
Oral and Gastrointestinal 315936 315936 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Diet and Nutrition 315937 315937 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dietary trial
Patient recruitment:
Suitable patients who consent to dietary trial and who meet the eligibility criteria outlined below will be enrolled into the dietary trial. We will aim to recruit 50 patients with functional dyspepsia diagnosed according to the internationally accepted Rome III criteria.

Initial clinical work up:
The following information will be collected from all patients prior to the dietary trial if not already available from the medical record:
- Serum sample for; a. FBC, CRP, ESR; b. tTG IgA, total IgA; c. HLA DQ2/8 status; d. anti-gliadin antibodies; e. wheat specific IgE; f. T cell subtype analysis
- Demographic and medical information
- Gastrointestinal symptoms from the phase 1 questionnaire (including nepean dyspepsia index, GI outpatient questionnaire, Rome III diagnostic questionnaire, IBS severity scoring system, hospital anxiety and depression scale, medication history)
- Dietary history
- Endoscopic and serum samples for immunological analysis
- Stool sample for microbiome analysis

For those who meet the inclusion and exclusion criteria will enter the dietary trial. The dietary trial is currently the only diagnostic test available for the diagnosis of non-coeliac gluten sensitivity, and this protocol is in accordance with the current international consensus guidelines.

Intervention steps;
1. Dietitian and trained physician review at enrolment. Patient educated by dietitian on following a gluten free, low FODMAP diet - resources provided (Clinic visit)
2. Symptom assessment at baseline using the Nepean Dyspepsia Index, IBS SSS, outpatient GI questionnaire and wheat sensitivity questionnaire
3. Participants to follow this gluten free, low FODMAP diet for 4 weeks - compliance measured using food diary in weekly follow up sessions. Gluten free diet resource provided to al participants is consistent with Coeliac Society guidlines and low FODMAP diet resource consistent with MonashFODMAP guidleines.
4. Symptom assessment will be done weekly during the run in diet using the wheat sensitivity questionnaire
5. Overall compliance to be reviewed after 4 weeks using GFD scoring tool and using a food diary for the adherence to the FODMAP component of the diet (Visit 2, HMRI)
6. For those whose dyspeptic symptoms respond to the run in diet, defined as a greater than 30% response in dyspeptic symptoms as measured by the modified Salerno wheat sensitivity questionnaire at visit 2;
a. Repeat serum testing of ESR and CRP
b. Repeat serum testing for immunological analysis
c. Repeat stool sample for microbiome analysis
7. These subjects will then proceed to move on to the dietary challenge stage: Double blind randomized placebo controlled crossover gluten and wheat challenge Cooked gluten and FODMAP will be administered in the form of a muesli bar (see 'food preparation') to be consumed as morning or afternoon tea daily while continuing gluten free, low FODMAP baseline diet
a. FODMAP depleted gluten15 g/day (commercially available)
b. High FODMAP, gluten free
c. Placebo 10-15g/day (no FODMAP, no gluten)
8. Patient provided with labelled study food to be taken home and stored in the freezer for the duration of the trial (visit 2)
9. Each challenge will be for 1 week, with 1 week washout between each challenge (6 weeks total). The order in which participants receive the study food will be randomized.
10. Participants will receive a phone call during each dietary challenge week (ie. fortnightly) to ensure compliance and ascertain presence of adverse effects
11. Symptom assessment will be done daily throughout trial using the specific wheat sensitivity questionnaire developed for the study in a mobile app format (Qualtrix) or paper based questionnaire
12. Visit at the end of the trial (Visit 3, week 7-8) to discuss the response to the trial (gluten/ FODMAP sensitivity)

Confirmation of food sensitivity
In those with a positive response to gluten or FODMAP, they may be challenged again with the causative food along with placebo to confirm the presence of a food sensitivity, to overcome the high nocebo response previously reported in trials of this type.

Study food preparation measures:
Recipes made with only gluten free ingredients (other than the gluten bar) with FODMAP contents tested by accredited facility, and confirmed as low FODMAP (except high FODMAP bar). All bars made with the same base ingredients which are gluten free and low FODMAP. The high FODMAP bar includes added inulin to replace a proportiong of rice flour and the high gluten bar contains gluten flour to replace a proportion of rice flour.
Food will be prepared by an accredited person who has been trained by the dietitian who developed the reciipes.
Food will be labelled and vacuum packed and stored in a freezer for 3 months at a time. Participants will be instructed to store the study food in their home freezer during the trial.

We anticipate that the dietary trial will yield four subsets of participants;
i. Gluten responsive functional dyspepsia (ie. non-coeliac gluten sensitivity)
ii. FODMAP responsive functional dyspepsia
iii. Gluten and FODMAP responsive functional dyspepsia
iv. Gluten and FODMAP unresponsive functional dyspepsia
Intervention code [1] 317841 0
Diagnosis / Prognosis
Comparator / control treatment
The placebo bar for the dietary trial is the low FODMAP, gluten free muesli bar. Recipes made with only gluten free ingredients (other than the gluten added bar) with FODMAP contents tested by accredited facility, and confirmed as low FODMAP (except high FODMAP bar). All bars made with the same base ingredients which are gluten free and low FODMAP. The high FODMAP bar includes added inulin to replace a proportiong of rice flour and the high gluten bar contains gluten flour to replace a proportion of rice flour.
Control group
Placebo

Outcomes
Primary outcome [1] 324144 0
Symptom measurement:
Run in diet: Those with a significant reduction in symptoms after the run-in diet (defined as >30% reduction in NDI score) were eligible for the rechallenge phase.
Dyspeptic symptoms were measured daily during the rechallenge phase and weekly during the washout weeks using a composite score of three numbered visual analog scale (VAS) (3 main symptoms; post-prandial fullness, epigastric pain, early satiety, each scored 0 – 10, total /30).
Timepoint [1] 324144 0
Run in phase: 4 weeks from baseline
Rechallenge phase: 10 weeks from baseline
Primary outcome [2] 324378 0
FODMAP sensitivity
Run in diet: Assessed only in combination with gluten (low FODMAP, gluten free) 4 weeks
Rechallenge: differentiated from gluten using symptom response to blinded crossover. FODMAP sensitivity will be assessed using daily symptom diary, cross checked against the type of bar once unblinded by the Research Assistant.
Timepoint [2] 324378 0
Run in phase: 4 weeks from baseline
Rechallenge phase: 10 weeks from baseline
Secondary outcome [1] 385785 0
Non diet responsive dyspeptic symptoms will be evidenced by maintenance of dyspeptic symptoms at the completion of the run-in diet (if dietary compliance is reported and evident from food diary).
Timepoint [1] 385785 0
4 weeks from baseline

Eligibility
Key inclusion criteria
Inclusion criteria:
1. Adults aged >18 years
2. Males and females
3. Functional dyspepsia; diagnosed by Rome III criteria
4. Were consuming a normal gluten and normal FODMAP containing diet for prior to their scheduled endoscopy and serum sample collection (as determined by the dietary evaluation using food frequency questionnaires and 24 hour recall questionnaire collected in phase 1)
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
1. Inflammatory bowel disease
2. Coeliac disease; negative TTG and/or absence of villous atrophy D2 biopsy at endoscopy
3. Current or previous gastrointestinal malignancy
4. Peptic ulcer disease
5. Systemic inflammatory condition
6. Diabetes mellitus
7. Wheat allergy; positive IgE specific serum test
8. Food avoidance as determined by dietary evaluation in phase 1 of the study
9. Immunosuppression
10. Active infection
11. Pregnant patients

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Numbered packaging, conducted by blinded research assistant
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated algorithm
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Our sample size calculation is based on the hypothesis that a dietary trigger is responsible for symptoms with FD, and that the dietary response would be due to gluten or FODMAP intake. Using repeated measures analysis of variance, with a power of 0.8 and a significance of 0.025 (0.05/2 for dual hypothesis) and a delta of 0.5, we calculate that we required 41 subjects to enter the dietary challenge phase of the trial. Assuming that 30% of subjects would not respond to the run-in diet and be eliminated, we estimated 58 participants would need to commence the study. Statistical analysis will be performed using STATA software (StataCorp, Texas, USA).
Changes in FODMAP intake and symptoms between run-in and diet phase will be evaluated via repeated measures analysis of variance. Association between baseline factors and change in symptoms will be evaluated via linear regression.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/10/2019
Actual
1/10/2019
Date of last participant enrolment
Anticipated
1/07/2022
Actual
Date of last data collection
Anticipated
1/12/2022
Actual
Sample size
Target
58
Accrual to date
30
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 16921 0
John Hunter Hospital - New Lambton
Recruitment postcode(s) [1] 30576 0
2305 - New Lambton

Funding & Sponsors
Funding source category [1] 305976 0
University
Name [1] 305976 0
The University of Newcastle
Country [1] 305976 0
Australia
Primary sponsor type
University
Name
The University of Newcastle
Address
Hunter Medical Research Institute
Kookaburra Circuit
New Lambton Heights NSW 2305
Country
Australia
Secondary sponsor category [1] 306437 0
None
Name [1] 306437 0
Address [1] 306437 0
Country [1] 306437 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306216 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 306216 0
Hunter Medical Research Institute
Kookaburra Circuit
New Lambton Heights NSW 2305
Ethics committee country [1] 306216 0
Australia
Date submitted for ethics approval [1] 306216 0
01/02/2018
Approval date [1] 306216 0
01/05/2018
Ethics approval number [1] 306216 0

Summary
Brief summary
Functional dyspepsia (FD), characterised by symptoms of epigastric pain or early satiety and post prandial distress, has been associated with duodenal eosinophilia, raising the possibility that it is driven by an environmental allergen. Non-coeliac gluten or wheat sensitivity (NCG/WS) has also been associated with both dyspeptic symptoms and duodenal eosinophilia, suggesting an overlap between these two conditions. The aim of this study is to evaluate the role of wheat (specifically gluten and fructans) in symptom reduction in participants with FD in a pilot randomized double-blind, placebo controlled, dietary crossover trial.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103130 0
Dr Kerith Duncanson
Address 103130 0
The University of Newcastle
Level 3 East
HMRI, New Lambton Heights, NSW, 2305
Country 103130 0
Australia
Phone 103130 0
+61428848264
Fax 103130 0
Email 103130 0
[email protected]
Contact person for public queries
Name 103131 0
Kerith Duncanson
Address 103131 0
The University of Newcastle
Level 3 East
HMRI, New Lambton Heights, NSW, 2305
Country 103131 0
Australia
Phone 103131 0
+61428848264
Fax 103131 0
Email 103131 0
[email protected]
Contact person for scientific queries
Name 103132 0
Kerith Duncanson
Address 103132 0
The University of Newcastle
Level 3 East
HMRI, New Lambton Heights, NSW, 2305
Country 103132 0
Australia
Phone 103132 0
+61428848264
Fax 103132 0
Email 103132 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not approved in ethics


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
8247Study protocol    380018-(Uploaded-17-06-2020-10-46-53)-Study-related document.docx



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