Desensitising Celiac Disease Patients With the Human Hookworm (NaCeD)
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| ClinicalTrials.gov Identifier: NCT01661933 |
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Recruitment Status :
Completed
First Posted : August 10, 2012
Results First Posted : October 13, 2014
Last Update Posted : October 20, 2014
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Sponsor:
The Prince Charles Hospital
Collaborator:
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
Dr John Croese, The Prince Charles Hospital
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Brief Summary:
We have established that the hookworm Necator americanus (Na) dramatically alters the local and systemic immune landscape of the infected human host. Consistent with the principle of desensitisation, diet managed celiac disease subjects previously infected by us with Na will be invited to receive small incremental doses of gluten as pasta (3-25 mm straw of spaghetti) over 16 weeks. Each participant will then be carefully re-assessed to determine if it is appropriate to undertake a 12-week gluten challenge.
| 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) |
| Primary Purpose: | Prevention |
| 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 |
Resource links provided by the National Library of Medicine
Genetics Home Reference related topics:
Celiac disease
MedlinePlus related topics:
Celiac Disease
| Arm | Intervention/treatment |
|---|---|
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Experimental: Necator americanus, gluten challenge
Single arm, vertical.
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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 |
Primary Outcome Measures :
- 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.
Secondary Outcome Measures :
- 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.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Previously enrolled adults who received an experimental hookworm infection with diet treated celiac disease.
Exclusion Criteria:
- Immune suppressive therapies
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01661933
Locations
| Australia, Queensland | |
| Prince Charles Hospital | |
| Chermside, Queensland, Australia, 4032 | |
Sponsors and Collaborators
The Prince Charles Hospital
National Health and Medical Research Council, Australia
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 |
Additional Information:
Publications:
| Responsible Party: | Dr John Croese, Chief Investigator, The Prince Charles Hospital |
| ClinicalTrials.gov Identifier: | NCT01661933 History of Changes |
| Other Study ID Numbers: |
AU/3/BOBD012 |
| First Posted: | August 10, 2012 Key Record Dates |
| Results First Posted: | October 13, 2014 |
| Last Update Posted: | October 20, 2014 |
| Last Verified: | October 2014 |
Keywords provided by Dr John Croese, The Prince Charles Hospital:
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celiac disease hookworm probiotic |
Additional relevant MeSH terms:
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Celiac Disease Malabsorption Syndromes Intestinal Diseases |
Gastrointestinal Diseases Digestive System Diseases Metabolic Diseases |