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
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- Enrollment
- 54
- Locations
- 4
- Primary Endpoint
- Safety of 30-week gluten challenge
Study Overview
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.
Detailed Description
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.
Aim 1&2/Clinical study: 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%.
Secondary outcomes include safety of low and medium intensity hookworm infection at intermediate (12 weeks and 24 weeks) endpoints of an escalating gluten challenge, assessed by incidence of adverse events, serious adverse events as well as general health. Secondary outcome measures include changes in V:C ratio from baseline to intermediate endpoints, progression through successful gluten challenge phases of the trial including a liberal diet, mucosal intraepithelial lymphocyte count, Celiac Symptom Index (CSI questionnaire), Celiac-Quality of Life Score (QOL questionnaire) and the serum immunoglobulin A (IgA) tissue transglutaminase (tTG) level of all cohorts.
Aims 3&4/Associated in vitro cell measures and ex vivo mucosal stimulation investigations: The associated studies are designed to more fully explore the immunological processes underpinning the clinical outcomes, and to take advantage of mucosal tissue collected in excess of the clinical requirements to test individual components of hookworm secretions which we believe hold great potential as future therapies. These experiments are complex and often depend on the quality of tissue and the cells collected.
Study Procedure: After written informed consent is obtained at the screening visit and prior to enrolment Participants may require some haematological work to confirm eligibility. Participants will be randomized to receive hookworm larvae (L3-10 or L3-20) suspended in 2-3 drops of water applied to the skin and covered with a light dressing, or Tabasco® Sauce in solution (Placebo Comparator). Before inoculation, each Participant will complete a QOL questionnaire, submit a fresh faecal specimen, and undergo a blood draw and duodenal biopsy. Thereafter each week for the duration of participation, a food diary and CSI questionnaire will be submitted. At designated times, gluten will be introduced in escalating volumes. Blood, faecal and biopsy collections, and a QOL questionnaire will also be collected. To better evaluate the independent effect of L3 on host immunity, the L3-20 cohort will undergo an endoscopy at week 12 in lieu of the week 36 intervention.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Re-identifiable IP containers
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- •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
Exclusion Criteria
- •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.
Arms & Interventions
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.
Intervention: Gluten micro-challenge (Other)
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.
Intervention: Moderate gluten challenge (Other)
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.
Intervention: Inadvertent gluten challenge (Other)
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.
Intervention: Gluten free diet (Other)
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.
Intervention: Liberal diet (Other)
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.
Intervention: Necator americanus-hookworm larvae L3-10 (Other)
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.
Intervention: Gluten free diet (Other)
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.
Intervention: Gluten micro-challenge (Other)
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.
Intervention: Inadvertent gluten challenge (Other)
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.
Intervention: Moderate gluten challenge (Other)
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.
Intervention: Tabasco® Sauce (Other)
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.
Intervention: Gluten micro-challenge (Other)
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.
Intervention: Inadvertent gluten challenge (Other)
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.
Intervention: Moderate gluten challenge (Other)
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.
Intervention: Liberal diet (Other)
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.
Intervention: Necator americanus-hookworm larvae L3-20 (Other)
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.
Intervention: Gluten free diet (Other)
Outcomes
Primary Outcomes
Safety of 30-week gluten challenge
Time Frame: 44 weeks
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%.
Secondary Outcomes
- Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42(38 weeks)
- Difference in V:C ratio between baseline (week -2) and week 42(14 weeks)
- Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 36(36 weeks)
- Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 94(94 weeks)
- Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 42(42 weeks)
- Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 42(46 weeks)
- Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 36(36 weeks)
- Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 36(40 weeks)
- Difference in Immunoglobulin A tissue transaminase (tTG) between baseline (week -4) and week 94(98 weeks)
- Difference in Celiac Symptom Index (CSI Questionnaire) between baseline (week 0) and week 42(42 weeks)
- Difference in V:C ratio between baseline (week -2) and week 12(14 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)
- Difference in Celiac-Quality of Life Score (QOL questionnaire) between baseline (week 0) and week 94(94 weeks)
- Difference in V:C ratio between baseline (week -2) and week 24(38 weeks)
- Difference in V:C ratio between baseline (week -2) and week 94(96 weeks)
- Difference in mucosal intraepithelial lymphocyte count between baseline (week -2) and week 42(14 weeks)