Desensitising Celiac Disease Patients With the Human Hookworm (NaCeD)
|ClinicalTrials.gov Identifier: NCT01661933|
Recruitment Status : Completed
First Posted : August 10, 2012
Results First Posted : October 13, 2014
Last Update Posted : October 20, 2014
|Condition or disease||Intervention/treatment||Phase|
|Celiac Disease||Biological: Necator americanus||Phase 1 Phase 2|
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 :||Interventional (Clinical Trial)|
|Actual Enrollment :||12 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||Single (Outcomes Assessor)|
|Official Title:||Combining Necator Americanus With Trace Gluten to Restore Tolerance in Coeliac Disease: a Pilot Clinical and a Detailed in Vitro Immunological Study.|
|Study Start Date :||August 2012|
|Actual Primary Completion Date :||March 2014|
|Actual Study Completion Date :||March 2014|
Experimental: Necator americanus, gluten challenge
Single arm, vertical.
Biological: Necator americanus
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 Name: Hookworm
Biological: Necator americanus
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 Name: Hookworm
- 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.
- 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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01661933
|Prince Charles Hospital|
|Chermside, Queensland, Australia, 4032|
|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|