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Hookworm Therapy for Coeliac Disease (NainCeD-3)

This study is not yet open for participant recruitment.
See Contacts and Locations
Verified April 2016 by James Cook University, Queensland, Australia
Sponsor:
Collaborators:
Townsville Hospital
The Prince Charles Hospital
Christchurch Hospital
Logan Hospital, Queensland
Australian Institute of Tropical Health and Medicine
QIMR Berghofer Medical Research Institute
National Health and Medical Research Council, Australia
Information provided by (Responsible Party):
James Cook University, Queensland, Australia
ClinicalTrials.gov Identifier:
NCT02754609
First received: April 26, 2016
Last updated: August 22, 2016
Last verified: April 2016
  Purpose

This trial is a Phase 1b multicentre, multinational, randomized, double-blind with single-blind arm and open label extension phase, placebo controlled, clinical trial evaluating the safety and predictability of an escalating gluten consumption to activate Coeliac Disease (CeD) in (a) a small cohort of people with diet-managed CeD treated with a placebo (n=10), and in (b) cohorts following low (L3-10; n=40) and medium (L3-20; n=10) dose hookworm inocula.

The investigators 4 aims for the study are:

Aim 1: Undertake a multiple-phase and escalating gluten challenge assessing safety to gluten exposure in hookworm-naïve and hookworm-infected people with CeD.

Aim 2: This phase Ib study recognizes that the evidence supporting this novel intervention is rudimentary and addresses amongst others the following questions: (a) The importance of L3 dose on Participant health, and (b) the importance of L3 dose on the safety of escalating gluten challenge and (c) the need for a comparator group should a phase II trial be warranted.

Aim 3: Examine the changes in intestinal T cell responses induced by hookworm infection and gluten exposure.

Aim 4: Assess the impact of hookworm infection and purified hookworm-derived proteins on gluten peptide-specific immune responses ex vivo.


Condition Intervention Phase
Celiac Disease Other: Gluten micro-challenge Other: Inadvertent gluten challenge Other: Moderate gluten challenge Other: Liberal diet Other: Necator americanus-hookworm larvae L3-10 Other: Tabasco® Sauce Other: Necator americanus-hookworm larvae L3-20 Other: Gluten free diet Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Hookworm Therapy for Coeliac Disease: A Phase 1B Safety and Dose-ranging Clinical Trial Examining Sustained Gluten Consumption in Hookworm-naive and Hookworm-infection People With Coeliac Disease

Resource links provided by NLM:


Further study details as provided by James Cook University, Queensland, Australia:

Primary Outcome Measures:
  • Difference in V:C ratio between baseline (week -2) and week 42 [ Time Frame: 44 weeks ]
    This primary outcome is to assess the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 42 to assess the effect of moderate gluten in participants who have received placebo, L3-10 or L3-20 hookworms.


Secondary Outcome Measures:
  • Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 12 [ Time Frame: 14 weeks ]
    This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 36 to assess the safety of administrating L3-20 hookworms.

  • Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 36 [ Time Frame: 38 weeks ]
    This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 36 to assess the effect of inadvertent gluten in participants who have received placebo or L3-10 hookworms.

  • Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42 [ Time Frame: 44 weeks ]
    This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 42 to assess the effect of moderate gluten in all participants.

  • Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 94 [ Time Frame: 96 weeks ]
    This secondary outcome is the mucosal intraepithelial lymphocyte count measured from tissue collected per-endoscopy comparing baseline (week -2) to week 94 to assess the effect of a liberal diet in participants who have received hookworm L3-10 or L3-20 hookworms.

  • Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 36 [ Time Frame: 36 weeks ]
    This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 36 to assess the effect of inadvertent gluten in all participants.

  • Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 42 [ Time Frame: 42 weeks ]
    This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 42 to assess the effect of moderate gluten in all participants.

  • Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 94 [ Time Frame: 94 weeks ]
    This secondary outcome is the analysis of the weekly CSI questionnaire from baseline (week 0) to week 42 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.

  • Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 36 [ Time Frame: 36 weeks ]
    This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 36 to assess the effect of inadvertent gluten in all participants.

  • Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 42 [ Time Frame: 42 weeks ]
    This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 42 to assess the effect of moderate gluten in all participants.

  • Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 94 [ Time Frame: 94 weeks ]
    This secondary outcome is the analysis of the QOL questionnaire from baseline (week 0) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.

  • Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 36 [ Time Frame: 40 weeks ]
    This secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 36 to assess the effect of inadvertent gluten in all participants.

  • Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 42 [ Time Frame: 46 weeks ]
    This secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 42 to assess the effect of moderate gluten in all participants.

  • Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 94 [ Time Frame: 98 weeks ]
    The secondary outcome is the analysis of the Immunoglobulin A tissue transaminase (tTG) level measured in serum from baseline (week -4) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.

  • Difference in V:C ratio between baseline (week -2) and week 36 [ Time Frame: 38 weeks ]
    This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 36 to assess the effect of inadvertent gluten in participants who have received placebo or L3-10 hookworms.

  • Difference in V:C ratio between baseline (week -2) and week 94 [ Time Frame: 96 weeks ]
    This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 94 to assess the effect of a liberal diet in participants who have received L3-10 or L3-20 hookworms.

  • Difference in V:C ratio between baseline (week -2) and week 12 [ Time Frame: 14 weeks ]
    This secondary outcome assesses the duodenal mucosal villous height to crypt depth ratio (V:C) measured from tissue collected per-endoscopy comparing baseline (week -2) to week 12 to assess the safety of administrating L3-20 hookworms.


Estimated Enrollment: 60
Study Start Date: September 2016
Estimated Study Completion Date: December 2020
Estimated Primary Completion Date: December 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Necator americanus-hookworm larvae L3-10
A total of 40 participants week 0 and week 8 will have low dose hookworms present in 2-3 drops of water applied to their skin and then covered in a light dressing. The hookworms are Necator americanus-hookworm larvae L3; 10 L3 in 200 microliter (uL) of deionized water presented in an Eppendorf tube. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge. At week 42, participants will have the option of going on the liberal diet.
Other: Gluten micro-challenge
From week 12 to week 24, all participants will start a gluten micro-challenge from 10mg/day for the first 2 weeks escalating over the this period to 50mg/day at the end of week 24.
Other: Inadvertent gluten challenge
From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.
Other: Moderate gluten challenge
From week 36 to week 42, all participants will be on gluten 2g/day.
Other: Liberal diet
From week 42, all participants will be unblinded and those who have received hookworm therapy have the option to go on a liberal diet of more than 10g of gluten/day from week 42 to week 94.
Other: Necator americanus-hookworm larvae L3-10
A total of 40 participants at week 0 and week 8 will have hookworms L3-10 present in 2-3 drops of water applied to their skin and then covered in a light dressing.
Other: Gluten free diet
From week 0 to week 12, all participants will be on a gluten free diet.
Placebo Comparator: Tabasco® Sauce
A total of 10 participants at week 0 and week 8 will have Tabasco® Sauce present in 2-3 drops of water applied to their skin and covered in a light dressing. Tabasco® Sauce is an ideal placebo as the sensation to the skin is similar to a hookworm. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge.
Other: Gluten micro-challenge
From week 12 to week 24, all participants will start a gluten micro-challenge from 10mg/day for the first 2 weeks escalating over the this period to 50mg/day at the end of week 24.
Other: Inadvertent gluten challenge
From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.
Other: Moderate gluten challenge
From week 36 to week 42, all participants will be on gluten 2g/day.
Other: Tabasco® Sauce
Arm: Placebo Comparator: Tabasco® Sauce A total of 10 participants at week 0 and week 8 will have Tabasco® Sauce present in 2-3 drops of water applied to their skin and covered in a light dressing
Other: Gluten free diet
From week 0 to week 12, all participants will be on a gluten free diet.
Experimental: Necator americanus-hookworm larvae L3-20
A total of 10 participants at week 0 and week 8 will have medium dose hookworms present in 2-3 drops of water applied to their skin and then covered in a light dressing. The hookworms are Necator americanus-hookworm larvae L3; 20 L3 in 200 uL of deionized water presented in an Eppendorf tube. All participants will undergo interventions of Gluten free diet, Gluten micro-challenge, Inadvertent gluten challenge and Moderate gluten challenge. At week 42, participants will have the option of going on the liberal diet.
Other: Gluten micro-challenge
From week 12 to week 24, all participants will start a gluten micro-challenge from 10mg/day for the first 2 weeks escalating over the this period to 50mg/day at the end of week 24.
Other: Inadvertent gluten challenge
From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.
Other: Moderate gluten challenge
From week 36 to week 42, all participants will be on gluten 2g/day.
Other: Liberal diet
From week 42, all participants will be unblinded and those who have received hookworm therapy have the option to go on a liberal diet of more than 10g of gluten/day from week 42 to week 94.
Other: Necator americanus-hookworm larvae L3-20
A total of 40 participants at week 0 and week 8 will have hookworms L3-20 present in 2-3 drops of water applied to their skin and then covered in a light dressing.
Other: Gluten free diet
From week 0 to week 12, all participants will be on a gluten free diet.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Has provided written informed consent and is willing to comply with all Protocol scheduled visits, treatment plan, laboratory tests, and other trial procedures and in the opinion of the Investigator has a good understanding of the Protocol, the length of the study and the demands of the study.
  2. Aged between 18-80 (at time of consent);
  3. Have a pre-treatment histological diagnosis of Marsh grade 3 CeD;
  4. Have a pre-trial V:C >2.0;
  5. Have elevated tTG or endomysial Ab +ve pre-trial;
  6. Have been adherent to a gluten-free diet for >6 months pre-enrolment;
  7. Have a tTG <20 IU/mL (normal <15) at screening;
  8. Have a CSI <35 at screening;
  9. If female, has met either of criterion "a or b" below:

    1. If of non-childbearing potential, has met 1 of the following - Amenorrheic for at least 2 years, or has had a hysterectomy and/or bilateral oophorectomy at least 8 weeks prior to screening, or has had a tubal ligation at least 8 weeks prior to screening.
    2. If of childbearing potential, must be willing to use the acceptable methods of contraception and abide by the timelines as indicated
  10. In the opinion of the Investigator is in good general health

Exclusion Criteria:

  1. Have any finding at screening that in the opinion of the Investigator or medical monitor would compromise the safety of the Participant or affect their ability to adhere to protocol scheduled visits, treatment plan, laboratory tests, and other trial procedures.
  2. Have participated in any other clinical trial and/or have received an investigational drug or device within 30 days of screening.
  3. Have history or current evidence of any of the following: compromised respiratory function (chronic obstructive pulmonary disease, respiratory depression, signs or symptoms of hypoxia at screening); thyroid pathology (unless stabilized and euthyroid for >3 months at the time of screening); hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection; evidence of clinically significant chronic cardiac, hepatic or renal disease; psychiatric illness (poorly controlled); seizure disorder or any other chronic health issues that in the opinion of the Investigator would exclude the Participant from the trial.
  4. History of substance abuse or current substance abuse that in the opinion of the Investigator would exclude the Participant from the trial.
  5. Have a history of intolerance, allergy or hypersensitivity to the proposed placebo - Tabasco® Sauce or any of its known ingredients.
  6. Have a history of intolerance, allergy or hypersensitivity to the proposed anthelmintic - mebendazole.
  7. Have a history of intolerance, allergy or hypersensitivity to the proposed chemicals used in preparation of N.americanus - amphotericin B and Betadine that in the opinion of the Investigator would exclude the Participant from the trial.
  8. Current requirement for consistent use of anti-inflammatory drugs (includes prescription and over the counter medication >2 doses per week, that in the opinion of the Investigator would significantly alter the Participant's immunity), aspirin exceeding 125 mg/day or the use of immunotherapeutics;
  9. Diagnosis of cancer which has been in remission for < 5 years, excluding Participants with adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ.
  10. Poor venous access making the Participant unable to comply with the safety laboratory testing and/or endoscopy sedation requirements.
  11. Are an employee of the Sponsor, Investigator or study centre or immediate family of such employees or the Investigator.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02754609

Contacts
Contact: Paul Giacomin, Phd +61 7 4232 1868 Paul.Giacomin@jcu.edu.au
Contact: John Croese, MBBS, MD +61 7 3371 6164 mcroese@bigpond.net.au

Locations
Australia, Queensland
Prince Charles Hospital Not yet recruiting
Brisbane, Queensland, Australia, 4032
Contact: Tony Rahman, MA DIC PhD    +61 7 3139 4000    Tony.Rahman@health.qld.gov.au   
Logan Hospital Not yet recruiting
Logan, Queensland, Australia, 4131
Contact: Mark Norrie, MBChB, Phd    +61 7 3299 8899    Mark.Norrie@health.qld.gov.au   
Townsville Hospital Not yet recruiting
Townsville, Queensland, Australia, 4812
Contact: John Masson, MBChB    +61 7 4728 1740    jmasson@gastronq.com.au   
New Zealand
Christchurch Hospital Not yet recruiting
Christchurch, New Zealand, 4710
Contact: Richard Gearry, MB ChB, Phd    +64 3 364 0640    richard.gearry@cdhb.govt.nz   
Sponsors and Collaborators
James Cook University, Queensland, Australia
Townsville Hospital
The Prince Charles Hospital
Christchurch Hospital
Logan Hospital, Queensland
Australian Institute of Tropical Health and Medicine
QIMR Berghofer Medical Research Institute
National Health and Medical Research Council, Australia
Investigators
Principal Investigator: John Croese, MBBS, MD Prince Charles Hospital
  More Information

Responsible Party: James Cook University, Queensland, Australia
ClinicalTrials.gov Identifier: NCT02754609     History of Changes
Other Study ID Numbers: CT-2016-CTN-01363-1
Study First Received: April 26, 2016
Last Updated: August 22, 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by James Cook University, Queensland, Australia:
Celiac Disease
Necator americanus
Helminths
Autoimmunity
Clinical Trials, Phase I
Randomized Controlled Trial

Additional relevant MeSH terms:
Celiac Disease
Hookworm Infections
Malabsorption Syndromes
Intestinal Diseases
Gastrointestinal Diseases
Digestive System Diseases
Metabolic Diseases
Strongylida Infections
Secernentea Infections
Nematode Infections
Helminthiasis
Parasitic Diseases

ClinicalTrials.gov processed this record on August 18, 2017