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Trial registered on ANZCTR


Registration number
ACTRN12621000781842
Ethics application status
Approved
Date submitted
12/02/2021
Date registered
22/06/2021
Date last updated
17/06/2022
Date data sharing statement initially provided
22/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Research Study to Determine the Minimum Dose of Gluten that is Toxic to People with Coeliac Disease
Scientific title
A Double-Blind, Placebo-Controlled, Adaptive Dose-Response Study To Assess the Acute Effects of Gluten in Adults with Treated Coeliac Disease (“Gluten Threshold Study”)
Secondary ID [1] 303440 0
CDIHRP001.5
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coeliac Disease 320744 0
Condition category
Condition code
Inflammatory and Immune System 318583 318583 0 0
Other inflammatory or immune system disorders
Oral and Gastrointestinal 318987 318987 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
In this study, participants will be required to ingest a gelatin capsule by mouth containing a randomly allocated dose of gluten or placebo (no gluten) as part of three separate gluten challenges. Either one or two gelatin capsules will be administered with the dose evenly distributed to achieve the specific dose. All doses will be administered to participants under direct supervision of study staff.

This research study will enroll participants into four different groups. Participants will be recruited and studied in sequential cohorts. Each Cohort will complete screening and intervention before participants in the subsequent cohorts are enrolled. Unblinded data from each completed cohort will be analysed to determine dose levels of gluten for the subsequent cohort.
- Group 1: 6 participants will undergo 3 gluten challenges requiring ingestion of 1g gluten (approximately half a slice of bread) at each challenge. Challenges will take place one month apart. This will be assessed first in 3 unmasked challenges at one-month intervals and is likely to provide a positive control” for IL-2 release. Analysis of serum IL-2 data from Cohort 1 will determine (1) the optimal assessment of serum IL-2 (either at baseline and one-time point after gluten, or serum pooled from collections at 2, 4, and 6 h), and (2) validate that a one-month interval between gluten challenges does not significantly alter IL-2 response strength.
- Group 2: 15 participants will undergo 3 gluten challenges requiring ingestion of either 0mg, 13mg, 90mg, or 610mg of gluten (approximately one-third of a slice of bread) at each challenge. Participants will be randomized to receive any of these doses (13mg, 90mg or 130mg or placebo 0mg. Challenges will take place one month apart.
- Groups 3 and 4: 15 participants in each cohort will undergo 3 gluten challenges requiring ingestion of up to 610mg of gluten (approximately one-third of a slice of bread) at each challenge. Altogether 12 patients will receive the high, medium, and low doses in one of their 3 food challenges, and 9 patients will receive a placebo (empty gelatin capsule) on one occasion in any order. The doses of gluten used in groups 3 and 4 are determined by the lowest dose of gluten to elicit an immune response in the previous group. Challenges will take place one month apart. Serum IL-2 responses to placebo will establish a cutoff level for the upper level of a negative response (for example mean + 3 standard deviation or a 95% confidence interval).

Participants who are randomly allocated to consume a dose of gluten in the gluten challenge will ingest gelatin capsules comprising vital wheat gluten and micro cellulose filler. Capsules will be administered under the direct supervision of study site staff. After ingesting the capsule, the participant will be observed for 6 hours and monitored for side effects. During the 6 hour observation period, participants will have blood collected at two-hourly intervals to measure immune response and will complete symptom questionnaires hourly. Urine will be collected to measure gluten molecules in the urine.

The gluten challenges will be administered by registered nurses and overseen by a medical doctor. Participants will be required to attend Wesley Medical Research in person for the 3 separate gluten challenges, in addition to a screening visit (to determine if the participant is suitable for the study) and an end of study visit. Gluten challenges will either be administered individually or with other participants.

The total duration of participation in the study is between 12 and 18 weeks.
Intervention code [1] 319742 0
Diagnosis / Prognosis
Comparator / control treatment
Participants may be randomly allocated to receive placebo as part of the gluten challenges. The placebo is a gelatin capsule containing no vital wheat gluten.
In each of the three gluten challenges, participants will be randomised to receive high, medium or low doses of gluten or placebo.
Control group
Placebo

Outcomes
Primary outcome [1] 326543 0
Maximum tolerated dose of gluten determined by elevation from baseline in serum IL-2 within 2 to 6 hours after ingestion
Timepoint [1] 326543 0
Baseline, 2 hours, 4 hours and 6 hours post-capsule ingestion for each challenge.
Secondary outcome [1] 391808 0
Change from baseline in severity of global gastrointestinal symptom score assessed by hourly patient-reported outcome (GLoSS) from baseline to 6 hours after gluten ingestion.
Timepoint [1] 391808 0
baseline, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours post gluten ingestion

Eligibility
Key inclusion criteria
1. Adults 25 to 75 years of age (inclusive) who have signed an informed consent form.
2. A history of Coeliac disease diagnosed on the basis of duodenal biopsy showing villous atrophy and abnormal coeliac disease-specific serology (anti-transglutaminase 2 IgA, deamidated gliadin peptide IgG, or anti-endomysial IgA.
3. Initiated gluten-free diet at least 2 years prior to screening.
4. No known gluten exposure within the previous one month at screening
5. No known allergy to gluten.
6. Willingness to consume up to 1 g of gluten (equivalent to about 1/2 slice of standard bread) at one time.
7. Willingness to undergo study procedures.
8. Able to read and understand English.
Minimum age
25 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Symptoms of fever, cough, shortness of breath, or suspicion of COVID-19 infection.
2. Known consumption of gluten-containing food within the previous one month.
3. Any medical condition or an immune-suppressing medical treatment taken within the previous 3 months that in the opinion of the investigator would impact the immune response (other than coeliac disease), confound interpretation of study results, or pose an increased risk to the patient. Topical or inhaled corticosteroids are acceptable.
4. Females who are pregnant, including those with positive urinary pregnancy test on the first day of screening.
5. Positive at Screening for both TGA and DGP-G serology tests, but note that elevation of one serology test is not an exclusion.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment by central randomisation by computer
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
Intervention assignment
Other
Other design features
The study will be divided into four parts in which patients will be recruited and studied in sequential cohorts. Unblinded data from each completed cohort will be analysed to determine dose levels of gluten for the subsequent cohort.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Primary Endpoint Analysis
For the purpose of defining serum IL-2 responders after gluten in interim analyses, and in the final analysis, all available data from placebo participants in the Per-protocol Population will be assessed. The method for arriving at the definition for IL-2 responder will be determined after the interim analysis for Cohort 2. It will be based on either the fold or numerical change from baseline for the peak, a selected time point, or average IL-2 concentration of pooled sera at 2, 4, and 6 hours after administration of placebo.
Estimating the maximum dose of gluten that does not cause immune activation will be based on a threshold active dose level of gluten that has at least one serum IL-2 responder, and on cells of 12 coeliac disease patients who do not elevate serum IL-2 after receiving one or a range of dose levels in the Fibonacci sequence below the threshold active dose. The threshold active dose level of gluten is assumed to be between 2 mg and 1000 mg. In successive cohorts, the range of doses tested narrows and the number of participants tested at individual dose levels increases. The threshold active dose level is revised if there are responders to lower dose levels. Ultimately, the threshold active dose level and the maximum dose of gluten with no IL-2 responders is expected to have been tested in 24 to 36 participants.

Analysis of the secondary endpoint, symptoms
Peak nausea and global gastrointestinal symptom severity for participants administered the threshold active dose level and the maximum inactive dose of gluten will be compared with 17 participants administered placebo in the Per-protocol Population.

Sample Size
In Cohort 1, if 21% of patients are IL-2 responders, then with a sample size of 6 there is an 80% chance at least one responder will be detected. For Cohort 2 to 4, with a total sample size of 24 participants tested at any particular dose of gluten, there is an 80% chance of detecting a responder if 6.5% of patients were IL-2 responders at that dose level of gluten.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/07/2021
Actual
29/07/2021
Date of last participant enrolment
Anticipated
29/07/2022
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
51
Accrual to date
6
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 18713 0
The Wesley Hospital - Auchenflower
Recruitment postcode(s) [1] 33157 0
4066 - Auchenflower

Funding & Sponsors
Funding source category [1] 307861 0
Other
Name [1] 307861 0
Wesley Medical Research
Country [1] 307861 0
Australia
Funding source category [2] 307863 0
Charities/Societies/Foundations
Name [2] 307863 0
Coeliac Australia
Country [2] 307863 0
Australia
Primary sponsor type
Other
Name
Wesley Medical Research
Address
Level 8, East Wing, The Wesley Hospital
451 Coronation Drive
Auchenflower, Qld 4066
Country
Australia
Secondary sponsor category [1] 308571 0
None
Name [1] 308571 0
Address [1] 308571 0
Country [1] 308571 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307864 0
UnitingCare Health Human Research Ethics Committee
Ethics committee address [1] 307864 0
Ethics committee country [1] 307864 0
Australia
Date submitted for ethics approval [1] 307864 0
08/01/2021
Approval date [1] 307864 0
08/03/2021
Ethics approval number [1] 307864 0
202105

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

Contacts
Principal investigator
Name 108742 0
Dr James Daveson
Address 108742 0
Level 8, East Wing
The Wesley Hospital
451 Coronation Drive
Auchenflower, Qld 4066
Country 108742 0
Australia
Phone 108742 0
+61 7 3721 1500
Fax 108742 0
Email 108742 0
James@coralseaclinical.com
Contact person for public queries
Name 108743 0
James Daveson
Address 108743 0
Level 8, East Wing
The Wesley Hospital
451 Coronation Drive
Auchenflower, Qld 4066
Country 108743 0
Australia
Phone 108743 0
+61 1800 363 677
Fax 108743 0
Email 108743 0
James@coralseaclinical.com
Contact person for scientific queries
Name 108744 0
James Daveson
Address 108744 0
Level 8, East Wing
The Wesley Hospital
451 Coronation Drive
Auchenflower, Qld 4066
Country 108744 0
Australia
Phone 108744 0
+61 1800 363 677
Fax 108744 0
Email 108744 0
James@coralseaclinical.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.