Inoculating Celiac Disease Patients With the Human Hookworm Necator Americanus: Evaluating Immunity and Gluten-sensitivity

NCT00671138 | Completed Phase 2 DMC

• 2 other identifiers: 2007/115IBD-0214R
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 3

Brief Summary

The disappearance of intestinal parasites from humans in developed countries may be responsible for the upsurge in many diseases including Celiac Disease, Crohn's, ulcerative colitis, asthma and hay fever. A parasite's survival relies on its ability to interfere with the host's immune response. The mechanisms employed to do this are similar to those required by a person to regulate against the so-called autoimmune disorders, diseases in which the system turns on itself. The investigators suspect that when parasites are excluded from the environment, some individuals become sufficiently self-reactive to develop an autoimmune disease. American researchers have successfully treated patients with Crohn's and ulcerative colitis using a pig whipworm (Trichuris suis). The investigators have undertaken a similar preliminary study using a human hookworm in Crohn's patients. Using a small group of healthy people with celiac disease, the investigators will test if a human hookworm, Necator americanus, inhibits immune responsiveness to gluten. Celiac disease is a very common autoimmune-like disease (1% of Americans are affected although only a minority are aware they have the condition). In this condition, an individual becomes reactive to gluten, a protein in foods derived from wheat, barley, oats and rye. What makes celiac disease such a good model for Crohn's disease is that similar immune changes are common to both, but in celiac disease the people are usually well, are not taking powerful immune suppressive drugs and the provocative antigens (the molecules that engage the immune system and provoke the disease) are known and can be excluded or introduced. As well as being of direct benefit to people with celiac disease, this study may give direction as to the potential of this parasite to manage inflammatory bowel disease. People with proven celiac disease who live in Brisbane, a modern Australian city, will be invited to participate. Enrollment will require that the candidate has been avoiding gluten for six months. The study is a blinded study (where the researchers and study subjects do not know who has gotten the parasites) aimed at comparing the disease activity and immunity after a controlled breach of the gluten-free diet in individuals with celiac disease, before and after hookworm infection. The disease severity and the immune system of celiac subjects before and after being inoculated with N. americanus will be examined using conventional and experimental investigations. This group's immunity will be compared to that of a group of matched, celiac control subjects (not infected with hookworm), before and after eating four pieces of standard white bread each day for three to five days. Twenty people, ten subjects per arm, will be recruited. Ten larvae initially, then five more after twelve weeks will be placed on the skin under a light dressing for thirty minutes. The investigators aim to test whether the hookworm infection will change the immune processes and suppress gluten sensitivity in people with celiac disease. Outcomes to be measured will be those that reflect the activity of celiac disease.

Conditions

Celiac Disease

Keywords

Celiac disease; Parasitic infections; necator americanus; Immunity

Outcome Measures

Primary Outcomes (1)

• Duodenal histology (Marsh classification) and rectal histology

  21 weeks

Secondary Outcomes (1)

• Peripheral blood mononuclear cells and mucosal lymphocytes will be grown ex vivo and challenged with gluten antigen immunodominant peptide. Cell proliferation and cytokine profiles will also be measured.

  21 weeks

Study Arms (2)

I

ACTIVE COMPARATOR

Arm I will be inoculated with the human hookworm necator americanus at weeks 0 and 12.

Biological: Necator americanus

II

PLACEBO COMPARATOR

Arm II participants will receive and identical sham-inoculums comprising a diluted amount of 0.2ml McIlhenny \& Co Tabasco Pepper Sauce®

Other: Sham inoculation

Interventions

Necator americanus BIOLOGICAL

10 necator americanus larvae will be inoculated at week 0 with a further 5 larvae inoculated at week 12

I

Sham inoculation OTHER

A diluted amount of McIlhenny \& Co Tabasco Pepper Sauce will be applied via a gauze dressing at weeks 0 and 12.

II

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of celiac disease
• Positive tTG (IgA)or positive anti IgA gliadin or anti-endomysial antibody test.
• Marsh score ≥3 on small bowel biopsy (subtotal villous atrophy)
• Clinical, biochemical or histological improvement on gluten free diet.
• Compliance with a gluten-free diet for 6 months lead-in.
• Lifestyle \& travel history indicative of a low risk for helminthic infection.
• Good general health not on immunomodifying agents.
• Ability to complete study
• Understand study \& risks
• Social supports
• Workplace flexibility
• Normal tTG at enrollment (\<10 dependent on serology)
• A HLA-DQ2 phenotype
• Negative fecal test for intestinal helminthes.
• Negative serological test for anti-strongyloides antibodies

You may not qualify if:

• Children (age \< 18)
• Immunomodulating medication in 6 months pre-enrollment
• Oral or intramuscular/intravascular steroids
• Regular weekly use of aspirin
• Regular weekly use of NSAID
• Regular weekly use of COXII inhibitors
• Regular weekly use of statin medications
• Clinical history indicating a likely need to use an immune suppressive agent during the course of the study.
• Unmanaged risk of pregnancy
• Past history of infection with helminthes (other than a past history of infection with the pinworm, Enterobius vermicularis)
• History of insulin dependent diabetes mellitus or Addison's disease
• History of anaphylaxis or severe allergic reactions
• Having received a vaccine within the preceding 30 days
• Positive strongyloides serology
• Iron deficiency anemia

Sponsors & Collaborators

• Princess Alexandra Hospital, Brisbane, Australia: lead
• The Broad Foundation: collaborator
• Townsville Hospital: collaborator
• James Cook University, Queensland, Australia: collaborator
• Walter and Eliza Hall Institute of Medical Research: collaborator
• Queensland Institute of Medical Research: collaborator

Study Sites (3)

Queensland Institute of Medical Research

Brisbane, Queensland, 4006, Australia

Location

Princess Alexandra Hospital

Brisbane, Queensland, 4102, Australia

Location

Logan Hospital

Logan City, Queensland, 4131, Australia

Location

Related Publications (2)

• Cantacessi C, Giacomin P, Croese J, Zakrzewski M, Sotillo J, McCann L, Nolan MJ, Mitreva M, Krause L, Loukas A. Impact of experimental hookworm infection on the human gut microbiota. J Infect Dis. 2014 Nov 1;210(9):1431-4. doi: 10.1093/infdis/jiu256. Epub 2014 May 3.

  PMID: 24795483 DERIVED

• Daveson AJ, Jones DM, Gaze S, McSorley H, Clouston A, Pascoe A, Cooke S, Speare R, Macdonald GA, Anderson R, McCarthy JS, Loukas A, Croese J. Effect of hookworm infection on wheat challenge in celiac disease--a randomised double-blinded placebo controlled trial. PLoS One. 2011 Mar 8;6(3):e17366. doi: 10.1371/journal.pone.0017366.

  PMID: 21408161 DERIVED

Related Links

• Broad Medical Research Program Website

MeSH Terms

Conditions

Celiac Disease; Parasitic Diseases

Interventions

ASP-1 protein, Necator americanus

Condition Hierarchy (Ancestors)

Malabsorption Syndromes; Intestinal Diseases; Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Infections

Study Officials

• John T Croese, FRACP MD

  The Townsville Hospital

  PRINCIPAL INVESTIGATOR

• A James M Daveson, MBBS

  Princess Alexandra Hospital

  STUDY DIRECTOR

• Alex Loukas, BSc Hon, PhD (UQ)

  Queensland Institute of Medical Research

  STUDY DIRECTOR

• James McCarthy, MBBS FRACP PhD

  Queensland Institute of Medical Research

  STUDY DIRECTOR

• Robert Anderson, MB ChB BMedSc PhD FRACP

  Walter & Eliza Hall Institute of Immunology

  STUDY DIRECTOR

• Graeme Macdonald, MBBS FRACP PhD

  Princess Alexandra Hospital

  STUDY DIRECTOR

• Soraya Gaze, BSc PhD

  Queensland Institute of Medical Research

  STUDY DIRECTOR

• Rick Speares, MBBS PhD

  Anton Breinl Centre for Public Health and Tropical Medicine, James Cook University, Townsville

  STUDY DIRECTOR

• Andrew Clouston, MBBS (Qld) PhD (Qld) FRCPA

  Envoi Pathology

  STUDY DIRECTOR

• Andrew Pascoe, B. Pharm, B.Sc, MBBS, FRACP

  Princess Alexandra Hospital

  STUDY DIRECTOR

• Geoffrey Cobert, BSc PhD

  Queensland Institute of Medical Research

  STUDY DIRECTOR

• Dianne Jones, RN RM BAppSc

  Princess Alexandra Hospital

  STUDY DIRECTOR

• Sharon Cooke, RN

  The Townsville Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Doctor

Study Record Dates

• First Submitted: May 1, 2008
• First Posted: May 5, 2008
• Study Start: October 1, 2007
• Primary Completion: December 1, 2008
• Study Completion: September 1, 2009
• Last Updated: February 2, 2016

Record last verified: 2016-01

Locations

AU (3)