Hookworm Therapy for Coeliac Disease

NCT02754609 | Completed Phase 1 DMC

• 1 other identifier: CT-2016-CTN-01363-1
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 4

Brief Summary

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.

Conditions

Celiac Disease

Keywords

Celiac Disease; Necator americanus; Helminths; Autoimmunity; Clinical Trials, Phase I; Randomized Controlled Trial

Outcome Measures

Primary Outcomes (1)

• Safety of 30-week gluten challenge

  The primary outcome will be the safety of an escalating 30-week gluten challenge in hookworm naïve or hookworm infected people with CeD following a medium-high dose hookworm infection, assessed by the change of duodenal villous height to crypt depth ratio (V:C) between pre-trial (week -2) and post-challenge (week 42). This will be a binary variable defined as safe if gluten challenge is completed and V:C ratio \>2.0 and there is \<20% change in its value from baseline or fail if drop out occurs prior to the completion of the gluten challenge or V:C ratio is \<2.0 or its change from baseline is \>20%.

  44 weeks

Secondary Outcomes (17)

• Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42

  14 weeks

• Difference in V:C ratio between baseline (week -2) and week 42

  14 weeks

• Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42

  38 weeks

• Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 36

  44 weeks

• Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 94

  96 weeks

Study Arms (3)

Necator americanus-hookworm larvae L3-10

EXPERIMENTAL

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; Other: Inadvertent gluten challenge; Other: Moderate gluten challenge; Other: Liberal diet; Other: Necator americanus-hookworm larvae L3-10; Other: Gluten free diet

Tabasco® Sauce

PLACEBO COMPARATOR

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; Other: Inadvertent gluten challenge; Other: Moderate gluten challenge; Other: Tabasco® Sauce; Other: Gluten free diet

Necator americanus-hookworm larvae L3-20

EXPERIMENTAL

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; Other: Inadvertent gluten challenge; Other: Moderate gluten challenge; Other: Liberal diet; Other: Necator americanus-hookworm larvae L3-20; Other: Gluten free diet

Interventions

Gluten micro-challenge OTHER

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.

Necator americanus-hookworm larvae L3-10; Necator americanus-hookworm larvae L3-20; Tabasco® Sauce

Inadvertent gluten challenge OTHER

From week 24 to week 36, all participants will be on gluten 50mg/day and 1g twice weekly.

Necator americanus-hookworm larvae L3-10; Necator americanus-hookworm larvae L3-20; Tabasco® Sauce

Moderate gluten challenge OTHER

From week 36 to week 42, all participants will be on gluten 2g/day.

Necator americanus-hookworm larvae L3-10; Necator americanus-hookworm larvae L3-20; Tabasco® Sauce

Liberal diet OTHER

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.

Necator americanus-hookworm larvae L3-10; Necator americanus-hookworm larvae L3-20

Necator americanus-hookworm larvae L3-10 OTHER

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.

Necator americanus-hookworm larvae L3-10

Tabasco® Sauce OTHER

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

Tabasco® Sauce

Necator americanus-hookworm larvae L3-20 OTHER

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.

Necator americanus-hookworm larvae L3-20

Gluten free diet OTHER

From week 0 to week 12, all participants will be on a gluten free diet.

Necator americanus-hookworm larvae L3-10; Necator americanus-hookworm larvae L3-20; Tabasco® Sauce

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Aged between 18-80 (at time of consent);
• Have a pre-treatment histological diagnosis of Marsh grade 3 CeD;
• Have a pre-trial V:C \>2.0;
• Have elevated tTG or endomysial Ab +ve pre-trial;
• Have been adherent to a gluten-free diet for \>6 months pre-enrolment;
• Have a tTG \<20 IU/mL (normal \<15) at screening;
• Have a CSI \<35 at screening;
• If female, has met either of criterion "a or b" below:
• 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.
• If of childbearing potential, must be willing to use the acceptable methods of contraception and abide by the timelines as indicated
• In the opinion of the Investigator is in good general health

You may not qualify if:

• 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.
• Have participated in any other clinical trial and/or have received an investigational drug or device within 30 days of screening.
• 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.
• History of substance abuse or current substance abuse that in the opinion of the Investigator would exclude the Participant from the trial.
• Have a history of intolerance, allergy or hypersensitivity to the proposed placebo - Tabasco® Sauce or any of its known ingredients.
• Have a history of intolerance, allergy or hypersensitivity to the proposed anthelmintic - mebendazole.
• 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.
• 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;
• 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.
• Poor venous access making the Participant unable to comply with the safety laboratory testing and/or endoscopy sedation requirements.
• Are an employee of the Sponsor, Investigator or study centre or immediate family of such employees or the Investigator.

Sponsors & Collaborators

• James Cook University, Queensland, Australia: lead
• Townsville Hospital: collaborator
• The Prince Charles Hospital: collaborator
• Christchurch Hospital: collaborator
• Logan Hospital, Queensland: collaborator
• Australian Institute of Tropical Health and Medicine: collaborator
• QIMR Berghofer Medical Research Institute: collaborator
• National Health and Medical Research Council, Australia: collaborator

Study Sites (4)

Prince Charles Hospital

Brisbane, Queensland, 4032, Australia

Location

Logan Hospital

Logan City, Queensland, 4131, Australia

Location

Townsville Hospital

Townsville, Queensland, 4812, Australia

Location

Christchurch Hospital

Christchurch, 4710, New Zealand

Location

MeSH Terms

Conditions

Celiac Disease; Autoimmune Diseases

Interventions

Diet, Gluten-Free

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Diet Therapy; Nutrition Therapy; Therapeutics; Diet; Nutritional Physiological Phenomena; Diet, Food, and Nutrition; Physiological Phenomena

Study Officials

• John Croese, MBBS, MD

  Prince Charles Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Re-identifiable IP containers
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Placebo, 20 hookworm L3 or 40 hookworm L3

Study Record Dates

• First Submitted: April 26, 2016
• First Posted: April 28, 2016
• Study Start: September 1, 2016
• Primary Completion: October 1, 2019
• Study Completion: October 1, 2019
• Last Updated: February 13, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3); NZ (1)