- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01661933
Desensitising Celiac Disease Patients With the Human Hookworm (NaCeD)
Combining Necator Americanus With Trace Gluten to Restore Tolerance in Coeliac Disease: a Pilot Clinical and a Detailed in Vitro Immunological Study.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Hypothesis The adaptive Th2/regulatory profile imposed by Na will promote gluten tolerance following a micro-dose desensitising programme.
Primary Aim: To determine the safety and efficacy of Na as a tolerising agent in celiac subjects
Specific Aim 1. Undertake a therapeutic pilot study comparing mucosal histopathology before and after a gluten challenge, to be preceded by a programmed desensitising micro-challenge using Na as a tolerising agent.
Specific Aim 2. Assess systemic and mucosal immune responses to gluten micro-challenge, Na infection, and gluten re-challenge throughout the pilot study, to be referenced against hookworm-naive people with treated and untreated celiac disease.
Specific Aim 3. Utilising blood and tissue from hookworm-naive celiac disease volunteers, undertake in vitro studies focusing on the effects of Na-derived excretory/secretory (ES) products on gluten-stimulated gut mucosal cell apoptosis, cytokine and gene profiles.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Queensland
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Chermside, Queensland, Australia, 4032
- Prince Charles Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Previously enrolled adults who received an experimental hookworm infection with diet treated celiac disease.
Exclusion Criteria:
- Immune suppressive therapies
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Necator americanus, gluten challenge
Single arm, vertical.
|
Previously inoculated subjects will be further inoculated as previously undertaken with 20 3rd stage infective Na larvae (10 + 10 over 4 weeks).
Four weeks after the 2nd inoculation, each participant will receive a micro-dose of gluten (10 mg daily) as pasta for 8 weeks, to be followed by a low-dose of gluten (50 mg daily) for 8 weeks.
After this, a detailed assessment involving upper endoscopy and duodenal biopsy will be performed before deciding on an individual case basis that it is safe for the participant to proceed to challenge.
A gluten challenge of 1 G (15-20 G of pasta or a ½ slice of standard white bread) twice weekly for 12 weeks will commence.
Other Names:
After completion of the previously planned challenge, volunteers will be invited to extend the gluten challenge.
The extension is for 4 weeks total.
The gluten challenge is stepwise: gluten 10 mg daily for one week, 50 mg daily for one week and finally 3 grams daily for 2 weeks.
The outcome measure is serum tissue transglutaminase to be compared before and after the intervention.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Duodenal Villus Height:Crypt Depth
Time Frame: Week -24 to -36
|
Biopsies were fixed in neutral buffered formalin, processed and carefully orientated and embedded in paraffin wax.
Sections (3 µm) were stained with H&E.
Slides from both time-points were de-identified, shuffled and graded by Dr John Croese after which results from poorly orientated slides were verified by Dr Andrew Clouston.
The Vh:Cd ratios were measured on 5 randomly selected well-orientated sites.
The null hypothesis is that hookworm infection will not protect against mucosal damage following 12-week exposure to gluten in celiac disease.
|
Week -24 to -36
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Intraepithelial Lymphocyte Count
Time Frame: Week-24 and -36
|
Biopsies were fixed in neutral buffered formalin, processed and carefully orientated and embedded in paraffin wax.
Sections (3 µm) were stained with anti-CD3.
All slides were de-identified and graded by Dr John Croese.
The IEL percentages were measured on 2 or more randomly selected well-orientated villi.
The null hypothesis is that hookworm infection will not protect against mucosal IEL influx following 12-week exposure to gluten in celiac disease.
|
Week-24 and -36
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Number of Participants With 2 Points Increase in Marsh Score Post GC-1g
Time Frame: Longitudinal change between week-24 and week-36
|
The Marsh score is a defined but qualitative assessment assigned a value to allow for comparison.
The scores were evaluated by consensus between the primary (chief) investigator and the study pathologist.
The Marsh score was graded 0, 1, 2, 3A (assigned-4), 3B (-5) and 3C (-6); rage 1-6 with normal=0 and severe inflammation=6.
Because the scoring is vulnerable to artefact, only a 2-point shift was regarded as a significant intra-individual change.
The scores were graded after week-36 on biopsies de-identified shuffled.
An upward shift was interpreted to reflect a significant worsening of gluten-associated inflammation.
The comparison reported evaluated changes from baseline (week-24) to post-low-dose gluten challenge (week-24; GC-1g).
The objective for using the Marsh score was to identify individuals who might have experienced a severe worsening in pathology due to GC-1g that might not be reflected in the Vh:Cd group analysis.
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Longitudinal change between week-24 and week-36
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Serum Anti-tissue Transglutaminase Antibodies Measured as International Units/mL (IU/mL)
Time Frame: Anti-tTG IU/mL levels pre-trial, mid-trial and after 3 gram/day gluten challenge
|
The trial was extended with pre-trial and mid-trial anti-tTG antibody levels used to compare with the post-trial levels.
Anti-tTG is a serological measure of tissue transglutaminase-2 antibodies.
In active celiac disease, levels are increased.
In treated disease, levels are low (normal cut-off was <15 IU/mL).
A significant increase compared to baseline in tTG can be expected 2 weeks after consuming 3g of gluten daily for 2 weeks in people with celiac disease who have been maintaining a gluten-free diet, but who are not taking other treatment.
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Anti-tTG IU/mL levels pre-trial, mid-trial and after 3 gram/day gluten challenge
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Study Director: John Croese, MD, The Prince Charles Hospital, Centre for Biodiscovery and Molecular Development of Therapeutics
- Principal Investigator: Dianne Jones, BAppSc, Logan Hospital
- Principal Investigator: Alexander Loukas, PhD, Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- AU/3/BOBD012
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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