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Trial registered on ANZCTR


Registration number
ACTRN12618000393257
Ethics application status
Approved
Date submitted
21/02/2018
Date registered
16/03/2018
Date last updated
1/11/2019
Date data sharing statement initially provided
6/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety of a new variety of barley for participants with coeliac disease
Scientific title
A clinical study determining the safety and gut health benefits of a new variety of barley in participants with coeliac disease
Secondary ID [1] 293414 0
Nil known
Universal Trial Number (UTN)
U1111-1205-5083
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
coeliac disease 305567 0
Condition category
Condition code
Oral and Gastrointestinal 304793 304793 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The study is a dietary intervention trial during which participants with coeliac disease will be randomly assigned to one of two treatment groups and will consume daily for 8 weeks a serve of either the ultra low gluten (ULG) barley or a gluten-free (GF) control cereal. The amount of gluten ingested in the serve of ULG barley is about is 0.3mg; the amount of gluten in a sealed bag of cereal containing 11 serves is 3.3mg.
Over the last 15 years CSIRO has developed barley varieties with nearly undetectable gluten levels. In the hull-less variety we are examining in this clinical trial the level of gluten is so low (<5 ppm [parts per million]) that foods made exclusively from it would qualify as ‘gluten free’ under European and US international standards where foods containing less than 20 ppm gluten can carry that label. However in Australia due to the different legislative requirements foods here suitable for coeliac disease must be completely gluten free. A hulled variety of ULG barley is being cultivated commercially in Australia and used and sold in Germany in gluten-free beer (http://www.pionier-glutenfrei.de/). A healthy, high fibre grain safe for coeliacs and those avoiding gluten has significant potential to improve the diet of those individuals.
This study involves scientific and clinical staff from CSIRO and Flinders Medical Centre (FMC) Department of Gastroenterology. Participants will be screened at FMC to ensure they are healthy and avoiding gluten, and will attend information sessions with a clinical trial co-ordinator to discuss the study, and a research dietitian to explain the nutritional aspects of the study. Both these sessions will take about an hour each. During the first information session (and after consenting to participate) the participants will provide a blood sample which will be used to check they are generally healthy, and that their coeliac antibodies indicate they are not likely to be eating gluten. When the results are received from the laboratory the co-ordinator will contact the participants and if they are eligible arrange the information session with the dietitian. During the second information session the dietitian will discuss the dietary aspects of the study, the faecal collections and provide a booklet of instructions. They will also arrange for a portable freezer, faecal collection kits, investigational product (including serving size instructions) and kitchen balance to be delivered to the participant's home.
Participants will be asked to eat their serve of investigational product at breakfast when it can be mixed with fruit/yoghurt/milk/other cereal. If an individual can not eat their whole serve at breakfast they can divide their serve and eat at two meals each day during the entire study. During the first week the participants are advised to gradually introduce the new cereal to their diet (instructions provided) to enable their gut and microbiome to adjust to the changes in their diet. The dietitian will advise participants how to substitute the investigational product for carbohydrate-based foods containing similar amounts of energy to ensure weight changes for individuals during the study are under 3kg. When not consuming their investigational product the participants eat their normal, gluten free diet.
On two occasions (V1, V2) participants will undergo an endoscopy to enable biopsy of the duodenum. This will be done before the dietary intervention starts (V1), and again at the end of the 8 week intervention (V2). These biopsies will enable the assessment by a pathologist of the health of the lining of their duodenum. Participants will make two 48 hr faecal collections during the study to enable the effects of the cereals on gut health to be assessed (before V1 and V2). Participants will complete questionnaires about any possible gluten ingestion during the study, and questionnaires to assess any symptoms they may experience. They will also complete a compliance diary and will return the empty plastic bags and uneaten investigational product at the end of the 8 week intervention. Participants will initially attend FMC for the two information sessions, and then either FMC or Noarlunga Hospitals on two occasions for their endoscopies. Participants will give blood (for coeliac disease serology and health screening) twice (first screening visit, and V2). Participants who complete the study will be given $200 vouchers to compensate for inconvenience and time the study required, and those who complete the first endoscopy will be provided a $50 voucher. Parking and reasonable travel costs will also be reimbursed.
Intervention code [1] 299659 0
Treatment: Other
Comparator / control treatment
The placebo control will be a commercially available gluten-free cereal
Control group
Placebo

Outcomes
Primary outcome [1] 304012 0
Change in morphological assessment of the duodenal biopsies by analysis of stained slides by two specialist pathologists. This will provide measures of gluten-related intestinal damage and inflammation.
Timepoint [1] 304012 0
Biopsies will be collected by the gastroenterologist during endoscopies undertaken at baseline (immediately prior to commencing the dietary intervention) and after 8 weeks of consuming the intervention
Primary outcome [2] 304013 0
Changes in clinical symptoms as assessed by patient reported outcome measures (PROMs) questionnaires
Timepoint [2] 304013 0
Questionnaires will be completed at recruitment (about 1 month prior to first biopsy), immediately prior to first biopsy (baseline) and at the end of the 8 week dietary intervention
Primary outcome [3] 304881 0
Coeliac disease specific serum antibody levels (IgA anti-tissue transglutaminase (tTG) and anti-deamidated gliadin peptide IgG antibodies).
Timepoint [3] 304881 0
At screening/consent visit (approximately 4 weeks before intervention) and at the end of the 8 week dietary intervention
Secondary outcome [1] 340719 0
Changes in faecal measures will determine the effects of ULG barley on digestive health and will include calculation of faecal bulk passed during 48 hour collections, short chain fatty acid concentrations, gluten immunogenic peptide levels, pH, moisture % and, if indicated, microbial analyses.
Timepoint [1] 340719 0
Faecal samples (48 hour collections) will be collected twice: immediately prior to the first (baseline) biopsy and after 8 weeks of intervention before the second biopsy.
Secondary outcome [2] 340720 0
Three day weighed food diaries will provide comprehensive details of the nutrient intakes of the participants
Timepoint [2] 340720 0
These will be completed twice: once prior to the baseline endoscopy and the second after 8 weeks of dietary intervention prior to the second endoscopy
Secondary outcome [3] 343619 0
Changes in faecal short chain fatty acid concentrations will determine the effects of ULG barley on digestive health
Timepoint [3] 343619 0
Faecal samples (48 hour collections) will be collected twice: immediately prior to the first (baseline) biopsy and after 8 weeks of intervention before the second biopsy.

Eligibility
Key inclusion criteria
• Medically diagnosed coeliac disease (CD)
• Have followed a GF diet for at least 2 years confirmed by history and normal CD serology (see exclusion criteria for normal range) from sample collected at screening visit
• Males and females aged 18-75 years
• No history of illness for the past 4 weeks which will affect their fitness for endoscopy, and any diarrhoeal illness
• Understand the study and agree to participate
• Are prepared to adhere to gluten free diet for the 12 weeks of the run-in and study
• Able to attend FMC (or Noarlunga Hospital) on 4 occasions during the study
• Prepared to undergo 2 endoscopies
• Willing to consume one serve of about 60g of investigational product daily for 8 weeks
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Refractory coeliac disease (CD), severe CD complications (eg enteropathy associated T-cell lymphoma or active dermatitis herpetiformis lesions at the time of screening)
• Screening CD antibody serology results outside normal range: participants excluded if deamidated gliadin IgG (AGA) is >11 units/mL or if anti-tissue transglutaminase antibody (tTG-IgA) is >11 units/mL
• Other chronic inflammatory or functional gastrointestinal disease (eg symptomatic gastrointestinal reflux disease, inflammatory bowel disease, functional bowel disorders)
• Uncontrolled diabetes or autoimmune, psychiatric, neurological disease or chronic disease (eg HIV-AIDS or cancer other than skin cancer) that could interfere with assessments
• Extended absences due to travel or other commitments
• Reported lactating, pregnant or wish to become during the study. If a participant becomes pregnant during the trial they will be withdrawn
• Other than oral contraceptives use of other medications or over-the-counter supplements that in the opinion of the gastroenterologist may interfere with study outcomes, including antibiotics, non-steroidal anti-inflammatory drugs, medications that alter microbiota function for 2 months prior to and during the clinical intervention. Stable regular dose of non-steroidal anti-inflammatory drugs that were commenced prior to screening visit are allowed with approval of the Principal Investigator.
• Use of any immunosuppressive medications for 6 months prior to and during the clinical intervention
• Use of warfarin or enoxaparin. Use of direct oral anticoagulants like xarelto, apixaban, rivoraxaban and antiplatelet medications like clopidogrel, prasugrel and ticagrelor. Use of aspirin is allowed
• Received any experimental drug within 14 days of randomisation; in the case of biologics at least 6 months prior to randomisation

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation - study staff determining eligibility will allocate to next study ID number and are unaware of the treatment allocated to that number
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
The online program (http://biomath.info/power/prt.htmIf) was used to calculate the number of participants needed/group if the differences in response are compared (ie paired analysis: response in placebo group compared to response in treatment group [V1-V2]). The morphology of the duodenal biopsy samples (villus height/crypt depth ratio [Vh:CrD]) is a sensitive measure to determine if the ULG barley has a detrimental effect in individual coeliac participants. Using mean, SD (3.0, 0.62) from the literature, along with reduction of >20% in Vh/CrD ratio (ie 0.5) as unacceptable, to be 90% confident of detecting a difference of this size the study will need 19 participants/group (hence using 20/group without active coeliac disease to complete the study, plus exclusions due to baseline serology results; withdrawals).
Criteria have been set to undertake post hoc separate analysis on participants (estimated 5%) who have Vh/CrD indicating baseline gluten-induced damage with normal serology.
Data analysis will be undertaken by an expert statistician using an appropriate random effects model to allow for repeated measures on individual participants. The effects of covariates, including age, baseline measures, smoking and food intake variables will be investigated and adjustments made for these variables if necessary. The appropriate distributional assumptions will be established from the data. It is anticipated that data on concentrations will be log transformed to normality, while data on counts will be analysed using a Poisson distribution with correction for over-dispersion. The PROM results will be summarised using the standard published approaches. If transformation to normality proves impossible, for example where there are numerous zero values, appropriate non-parametric tests will be used.
All data will be provided to the statistician in de-identified format via REDCap.
Demographics will be tabulated and summarised. All clinical safety and tolerability data and treatment-emergent adverse events will be listed and summarized. The level and timing of participant withdrawal from both intervention groups will be summarized. Compliance will be assessed by the amount of product returned and diary records. Protocol deviations will be summarised and impact reviewed.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
19/11/2018
Actual
19/11/2018
Date of last participant enrolment
Anticipated
19/10/2020
Actual
Date of last data collection
Anticipated
18/12/2020
Actual
Sample size
Target
62
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 10082 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 21608 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 298039 0
Commercial sector/Industry
Name [1] 298039 0
The Healthy Grain
Country [1] 298039 0
Australia
Primary sponsor type
Government body
Name
CSIRO Health and Biosecurity
Address
PO Box 10041
Adelaide BC 5000
Country
Australia
Secondary sponsor category [1] 297945 0
Hospital
Name [1] 297945 0
Flinders Medical Centre
Address [1] 297945 0
Flinders Medical Centre
Flinders Drive
Bedford Pk South Australia 5042
Country [1] 297945 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299066 0
Southern Adelaide Clinical Human Research Ethics Committee (SAC HREC)
Ethics committee address [1] 299066 0
Ethics committee country [1] 299066 0
Australia
Date submitted for ethics approval [1] 299066 0
27/02/2018
Approval date [1] 299066 0
26/06/2018
Ethics approval number [1] 299066 0
OFR Number: 54.18 HREC Ref Number: HREC/18/SAC/65
Ethics committee name [2] 299701 0
CSIRO Health and Medical (CHM HREC)
Ethics committee address [2] 299701 0
Ethics committee country [2] 299701 0
Australia
Date submitted for ethics approval [2] 299701 0
17/08/2018
Approval date [2] 299701 0
28/08/2018
Ethics approval number [2] 299701 0
Proposal RR 23/2018

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 79174 0
Dr Dr SzePheh Yeap
Address 79174 0
Flinders Medical Centre
Flinders Drive
Bedford Pk South Australia 5042
Country 79174 0
Australia
Phone 79174 0
+ 61 8 8204 5511
Fax 79174 0
Email 79174 0
SzePheh.Yeap@sa.gov.au
Contact person for public queries
Name 79175 0
Crispin Howitt
Address 79175 0
CSIRO Agriculture and Food
GPO Box 1700, Canberra, ACT, 2601, Australia
Country 79175 0
Australia
Phone 79175 0
+61 2 6246 5032
Fax 79175 0
Email 79175 0
Crispin.Howitt@csiro.au
Contact person for scientific queries
Name 79176 0
Crispin Howitt
Address 79176 0
CSIRO Agriculture and Food
GPO Box 1700, Canberra, ACT, 2601, Australia
Country 79176 0
Australia
Phone 79176 0
+61 2 6246 5032
Fax 79176 0
Email 79176 0
Crispin.Howitt@csiro.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Undecided at this stage but likely de-identified individual participant data underlying published results only.
When will data be available (start and end dates)?
Access soon after publication of primary study manuscript.
The CSIRO Data Access Repository (DAP) is intended for long term storage of data, but this may be varied for individual projects.
Available to whom?
Requests for access to data for non-commercial purposes only will be considered on a case-by-case basis at the discretion of the project contact.
Available for what types of analyses?
At this stage available only to achieve the aims in the approved proposal and at the discretion of CSIRO's project contact.
How or where can data be obtained?
Mediated access via project contact via CSIRO's Data Access Portal (data.csiro.au). Access is likely to require signing of data access or license agreement.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.